Disease Information

General Information of the Disease (ID: DIS00512)

• Name: Liver cancer
• ICD: ICD-11: 2C12

Type(s) of Resistant Mechanism of This Disease

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Preclinical Drug(s) 1 drug(s) in total

Arenobufagin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Proprotein convertase subtilisin/kexin type 9 (PCSK9) [1]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Arenobufagin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vivo Model: Hepa1-6 hepatocellular carcinoma transplanted tumor model mice; Mice
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Key Molecule: Proprotein convertase subtilisin/kexin type 9 (PCSK9) [1]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Arenobufagin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vitro Model: Hepa1-6 cells; Liver; Mus musculus (Mouse); CVCL_0327
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Approved Drug(s) 9 drug(s) in total

Lenvatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Acylphosphatase 1 (ACYP1) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.80E-05; Fold-change: 2.38E-01; Z-score: 4.38E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: LvACYP1 Hep3B cells lung metastasis model; LvACYP1 Hep3B cells xenograft model; LvCON Hep3B cells lung metastasis model; LvCON Hep3B cells xenograft model; Mice
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells.

Key Molecule: Acylphosphatase 1 (ACYP1) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.80E-05; Fold-change: 2.38E-01; Z-score: 4.38E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay; Cell colony formation assay
• Mechanism Description: Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells.

Key Molecule: Acylphosphatase 1 (ACYP1) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.80E-05; Fold-change: 2.38E-01; Z-score: 4.38E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Overall survival assay (OS)
• Mechanism Description: Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells.

Key Molecule: Acylphosphatase 1 (ACYP1) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.80E-05; Fold-change: 2.38E-01; Z-score: 4.38E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) [10]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Liquid chromatography mass spectrometry (LC-MS)
• Experiment for Drug Resistance: Modified response evaluation criteria in solid tumors (mRECIST)
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell prognosis assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: BCL2 interacting protein 3 (BNIP3) [11]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• Experiment for Molecule Alteration: Mitochondrial morphology assay; Mitophagy colocalization assay; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Of note, our transcriptome analyses showed that, in HCC cell competition scenario, lenvatinib-resistant cells captured the increased glycolysis activity but the attenuated oxidative phosphorylation level as well as decreased mitochondria mass; however, lenvatinib-sensitive cells obtain opposite metabolic features.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vitro Model: L-02 hepatic non-tumor cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: BCL2 interacting protein 3 (BNIP3) [11]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Six-week-old female BALB/c nude mice, Huh7R/PLC-PRF-5R; Mice
• Experiment for Molecule Alteration: Mitochondrial morphology assay; Mitophagy colocalization assay; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Of note, our transcriptome analyses showed that, in HCC cell competition scenario, lenvatinib-resistant cells captured the increased glycolysis activity but the attenuated oxidative phosphorylation level as well as decreased mitochondria mass; however, lenvatinib-sensitive cells obtain opposite metabolic features.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice, MHCC97-H cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) [10]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Hydrodynamic transfection mouse model; Mice
• Experiment for Molecule Alteration: Liquid chromatography?mass spectrometry (LC?MS)
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) [10]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Orthotopic HCC model with the glycolysis inhibitor 2-DG; Homo Sapiens
• Experiment for Molecule Alteration: Liquid chromatography mass spectrometry (LC-MS)
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

Key Molecule: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) [10]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IGF2BP3 knockdown Hep3B-LR cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: IGF2BP3 knockdown Huh7-LR cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Liquid chromatography?mass spectrometry (LC?MS)
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

Key Molecule: Acylphosphatase 1 (ACYP1) [2]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ACYP1 overexpression cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: SK-Hep1 cells; Ascites; Homo sapiens (Human); CVCL_0525
• In Vivo Model: ACYP1 knockdown nude mice; Mice
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Mechanistically, ACYP1 enhanced glycolysis by upregulating the expression of LDHA, and the upregulation of LDHA is MYC-dependent. Additionally, the stability of c-Myc can be attributed to the interaction of ACYP1 and HSP90. More importantly, the ACYP1/HSP90/MYC/LDHA axis is associated with lenvatinib resistance in HCC cells.

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Stearoyl-CoA desaturase (SCD) [3]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.73E-15; Fold-change: 7.96E-01; Z-score: 8.54E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Six-week-old male BALB/c athymic nude mice; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In this study, we found that HBXIP suppresses ferroptosis by inducing abnormal free FA accumulation and blocks the anti-cancer activity of sorafenib in HCC cells. Mechanistic investigation revealed that HBXIP acts as a coactivator to induce SCD expression via coactivating transcription factor ZNF263, leading to upregulation of FA biosynthesis. Overexpression of HBXIP prevents ferroptosis and reduces the anti-tumor effect of sorafenib in vivo and in vitro.

Key Molecule: Autophagy related 12 (ATG12) [4]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.44E-07; Fold-change: 2.13E-01; Z-score: 5.02E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results.

Key Molecule: Unconventional prefoldin RPB5 interactor (URI) [5]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.94E-12; Fold-change: 1.72E-01; Z-score: 7.26E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: JHH1 cells; Liver; Homo sapiens (Human); CVCL_2785
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell.

Key Molecule: Unconventional prefoldin RPB5 interactor (URI) [5]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.94E-12; Fold-change: 1.72E-01; Z-score: 7.26E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients with recurrent HCC; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Overall survival assay (OS)
• Mechanism Description: In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell.

Key Molecule: Unconventional prefoldin RPB5 interactor (URI) [5]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.94E-12; Fold-change: 1.72E-01; Z-score: 7.26E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: 1-year recurrence free survival rate
• Mechanism Description: In summary, URI keeps low levels of p53 in a TRIM28-MDM2 dependent manner, maintains SCD1 activity and accumulation of MUFAs, and subsequently promotes resistance to TKIs in cancer cell.

Key Molecule: L-glutamine amidohydrolase (GLS) [4]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Liver cancer
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.74E-22; Fold-change: 1.39E-01; Z-score: 1.12E+01
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results.

Key Molecule: Circular RNA UBE2D2 (circUBE2D2) [13]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: In conclusion, these findings demonstrate that circUBE2D2 accelerated the HCC glycolysis and sorafenib resistance via circUBE2D2/miR-889-3p/LDHA axis, which provides a novel approach for HCC treatment.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell prognosis assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: microRNA-494 (miR-494) [14]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• In Vivo Model: HCC patient; Homo Sapiens
• Experiment for Molecule Alteration: Real time PCR
• Experiment for Drug Resistance: Overall survival assay (OS)
• Mechanism Description: MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vivo Model: Four-week-old male B-NDG? mice, each subgroup of cells; Mice
• Experiment for Molecule Alteration: Western blot analysis; LC/MS
• Mechanism Description: In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl5 signaling pathway.

Key Molecule: Circular RNA UBE2D2 (circUBE2D2) [13]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Huh7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: SMMC-7721 cells; Liver; Homo sapiens (Human); CVCL_0534
• In Vitro Model: Lo-2 normal liver cells; Liver; Homo sapiens (Human); CVCL_C7SD
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In conclusion, these findings demonstrate that circUBE2D2 accelerated the HCC glycolysis and sorafenib resistance via circUBE2D2/miR-889-3p/LDHA axis, which provides a novel approach for HCC treatment.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vitro Model: Knockdown GPAT3 in Hep3B SR cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Knockdown GPAT3 in MHCC97H SR cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: ChIP and western blot
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• Experiment for Molecule Alteration: Western blot analysis; LC/MS
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl2 signaling pathway.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vitro Model: MHCC97H cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: Western blot analysis; LC/MS
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl3 signaling pathway.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis; LC/MS
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: In this study, we observed a significant increase in TAG accumulation in SR HCC cells. Through multi-omics analysis, we identified upregulated GPAT3 as the key enzyme involved in sorafenib resistance. Transcriptional activation of GPAT3 in SR is mediated by STAT3, which directly binds to the GPAT3 promoter. Loss- and gain-of-function experiments demonstrated that GPAT3 promotes sorafenib resistance in HCC by enhancing TAG-mediated NF-kappaB/Bcl4 signaling pathway.

Key Molecule: microRNA-494 (miR-494) [14]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• Experiment for Molecule Alteration: Real time PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions.

Key Molecule: Long intergenic non-protein coding RNA (HNF4A-AS1) [12]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• In Vitro Model: Huh7-R cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Gene set enrichment analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC.

Key Molecule: microRNA-23b-3p (miR-23b-3p) [4]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: NGS and real-time PCR demonstrated the downregulated expression of miR-23b-3p in sorafenib-resistant cells compared to parental cells. In silico analysis showed that miR-23b-3p specifically targeted autophagy through ATG12 and glutaminolysis through GLS1. In transfection assays, mimics of miR-23b-3p demonstrated reduced gene expression for both ATG12 and GLS1, decreased cell viability, and increased cell apoptosis of sorafenib-resistant HepG2 cells, whereas the antimiRs of miR-23b-3p demonstrated contrasting results.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: MHCC97H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: Sorafenib-resistant MHCC97H cells; Liver; Homo sapiens (Human); CVCL_4972
• Experiment for Molecule Alteration: ChIP and western blot
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vitro Model: L-02 hepatic non-tumor cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: microRNA-494 (miR-494) [14]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Spheroids formation assay
• Mechanism Description: Here, we confirmed the synergic effect of antimiR-494/sorafenib treatment and demonstrated for the first time that, together with AKT pathway repression, G6pc targeting mediates miR-494-induced sorafenib resistance in HCC cells. In line, the oncomiR-21 triggered sorafenib resistance in HCC cells by PTEN direct targeting or by regulating the nuclear localization of the long non-coding RNA SNHG1 [63].

Key Molecule: Glucose-6-phosphatase catalytic subunit (G6PC) [14]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Spheroids formation assay
• Mechanism Description: Here, we confirmed the synergic effect of antimiR-494/sorafenib treatment and demonstrated for the first time that, together with AKT pathway repression, G6pc targeting mediates miR-494-induced sorafenib resistance in HCC cells. In line, the oncomiR-21 triggered sorafenib resistance in HCC cells by PTEN direct targeting or by regulating the nuclear localization of the long non-coding RNA SNHG1 [63].

Key Molecule: AMP-activated protein kinase (AMPK) [16]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Activity; activation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh7-AMPKAR2 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: FRET-based high content imaging
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Our findings suggest that glycolysis promotes sorafenib resistance through maintaining AMPK activation.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vivo Model: MHCC97H subcutaneous tumor-bearing model; Mice
• Experiment for Molecule Alteration: ChIP and western blot
• Experiment for Drug Resistance: Tumor growth assay
• Mechanism Description: Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.

Key Molecule: Long intergenic non-protein coding RNA (HNF4A-AS1) [12]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Subcutaneous xenografts with HCC cells stably transfected with Lv-lnc-HNF4A-AS1 in nude mice; subcutaneous xenografts with HCC cells stably transfected with Lv-sh-HNF4A-AS1 in nude mice; Mice
• Experiment for Molecule Alteration: Gene set enrichment analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC.

Key Molecule: microRNA-494 (miR-494) [14]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• In Vivo Model: Diethylnitrosamine (DEN)-induced HCC rats; Diethylnitrosamine (DEN)-induced xenograft mice; Mice; Rats
• Experiment for Molecule Alteration: Real time PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: MiR-494 induced the metabolic shift of HCC cells toward a glycolytic phenotype through G6pc targeting and HIF-1A pathway activation. MiR-494/G6pc axis played an active role in metabolic plasticity of cancer cells, leading to glycogen and lipid droplets accumulation that favored cell survival under harsh environmental conditions.

Key Molecule: Glycerol-3-phosphate acyltransferase 3 (GPAT3) [15]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IL-17 signaling pathway; Activation; hsa04657
• Cell Pathway Regulation: EGFR tyrosine kinase inhibitor resistance; Activation; hsa01521
• In Vivo Model: SR xenografts, four-week-old male B-NDG? mice; control SR-MHCC97H group, four-week-old male B-NDG? mice; Mice
• Experiment for Molecule Alteration: ChIP and western blot
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.

Key Molecule: Hepatitis B virus X-interacting protein (HBXIP) [3]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Six-week-old male BALB/c athymic nude mice; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In this study, we found that HBXIP suppresses ferroptosis by inducing abnormal free FA accumulation and blocks the anti-cancer activity of sorafenib in HCC cells. Mechanistic investigation revealed that HBXIP acts as a coactivator to induce SCD expression via coactivating transcription factor ZNF263, leading to upregulation of FA biosynthesis. Overexpression of HBXIP prevents ferroptosis and reduces the anti-tumor effect of sorafenib in vivo and in vitro.

Key Molecule: Circular RNA UBE2D2 (circUBE2D2) [13]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male BALB/C nude mice; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In conclusion, these findings demonstrate that circUBE2D2 accelerated the HCC glycolysis and sorafenib resistance via circUBE2D2/miR-889-3p/LDHA axis, which provides a novel approach for HCC treatment.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Sorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice, MHCC97-H cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: AMP-activated protein kinase (AMPK) [16]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Sorafenib
• Molecule Alteration: Activity; inhibit
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Huh7-AMPKAR2 cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: FRET-based high content imaging
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Our findings suggest that glycolysis promotes sorafenib resistance through maintaining AMPK activation.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Polypyrimidine tract binding protein 1 (PTBP1) [6]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.36E-03; Fold-change: 6.44E-02; Z-score: 2.87E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• Cell Pathway Regulation: Glutamatergic synapse; Activation; hsa04724
• In Vitro Model: CA3 cells; Liver; Homo sapiens (Human); N.A.
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• In Vitro Model: SNU-182 cells; Liver; Homo sapiens (Human); CVCL_0090
• In Vitro Model: SNU-878 cells; Liver; Homo sapiens (Human); CVCL_5102
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Consistently, PTBP1 promotes glutamine uptake and the glutamine metabolism key enzyme, glutaminase (GLS) expression. Bioinformatics analysis predicted that the 3'-UTR of GLS mRNA contained PTBP1 binding motifs which were further validated by RNA immunoprecipitation and RNA pull-down assays. PTBP1 associated with GLS 3'-UTR to stabilize GLS mRNA in HCC cells. Finally, we demonstrated that the PTBP1-promoted CDDP resistance of HCC cells was through modulating the GLS-glutamine metabolism axis.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Proprotein convertase subtilisin/kexin type 9 (PCSK9) [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vivo Model: Hepa1-6 hepatocellular carcinoma transplanted tumor model mice; Mice
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Key Molecule: Proprotein convertase subtilisin/kexin type 9 (PCSK9) [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Hepatocellular carcinoma
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.96E-09; Fold-change: 4.92E-01; Z-score: 5.99E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cholesterol metabolism; Activation; hsa04979
• In Vitro Model: Hepa1-6 cells; Liver; Mus musculus (Mouse); CVCL_0327
• Experiment for Molecule Alteration: Western blot analysis and immunohistochemical assays
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: ARBU significantly inhibited the proliferation of Hepa1-6 in vivo and in vitro, regulated cholesterol metabolism, and promoted the M1-type polarization of macrophages in the tumor microenvironment. ARBU inhibits cholesterol synthesis in the TME through the PCSK9/LDL-R signaling pathway, thereby blocking macrophage M2 polarization, promoting apoptosis of the tumor cells, and inhibiting their proliferation and migration.

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: WNT/beta-catenin pathway; Regulation; N.A.
• In Vivo Model: HCC samples; Homo Sapiens
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Overall survival assay (OS)
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: WNT/beta-catenin pathway; Regulation; N.A.
• In Vivo Model: HCC samples; Homo Sapiens
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Recurrence-free survival assay
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC-LM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: ASPP2-silenced HCC-LM3 xenografts expressing shAspp2-Luc; ASPP2-silenced HCC-LM3 xenografts expressing shNon-Luc; Mice
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

Cabozantinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Cabozantinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell prognosis assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Cabozantinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vitro Model: L-02 hepatic non-tumor cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Cabozantinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice, MHCC97-H cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

IgG isotype

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Histone H3 [9]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: IgG isotype
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Immunocompetent mice inoculated with control Hepa1-6 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Histone H3 [9]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: IgG isotype
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Immunocompetent mice inoculated with shSrsf10 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: WNT/beta-catenin pathway; Regulation; N.A.
• In Vivo Model: HCC samples; Homo Sapiens
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Overall survival assay (OS)
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: WNT/beta-catenin pathway; Regulation; N.A.
• In Vivo Model: HCC samples; Homo Sapiens
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Recurrence-free survival assay
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCC-LM3 cells; Liver; Homo sapiens (Human); CVCL_6832
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

Key Molecule: Apoptosis-stimulating of p53 protein 2 (ASPP2) [8]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: ASPP2-silenced HCC-LM3 xenografts expressing shAspp2-Luc; ASPP2-silenced HCC-LM3 xenografts expressing shNon-Luc; Mice
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance.

PD-1 mAb

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Histone H3 [9]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: PD-1 mAb
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Control into wild-type C57B/6 mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity.

Key Molecule: Histone H3 [9]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: PD-1 mAb
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Immunocompetent mice inoculated with control Hepa1-6 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Histone H3 [9]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: PD-1 mAb
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: ShSrsf10 Hepa1-6 cells into wild-type C57B/6 mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity.

Key Molecule: Histone H3 [9]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: PD-1 mAb
• Molecule Alteration: Lactylation; H3K18la
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Immunocompetent mice inoculated with shSrsf10 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8 T cell activity.

Regorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Regorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell prognosis assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: Long intergenic non-protein coding RNA (HNF4A-AS1) [12]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Regorafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• In Vitro Model: Huh7-R cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Gene set enrichment analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Mechanistically, HNF4A-AS1 interacted with METTL3, leading to m6A modification of DECR1 mRNA, which subsequently decreased DECR1 expression via YTHDF3-dependent mRNA degradation. Consequently, decreased HNF4A-AS1 levels caused DECR1 overexpression, leading to decreased intracellular PUFA content and promoting resistance to sorafenib-induced ferroptosis in HCC.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Regorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: MHCC97-H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: MHCC97-L cells; Liver; Homo sapiens (Human); CVCL_4973
• In Vitro Model: L-02 hepatic non-tumor cells; Liver; Homo sapiens (Human); CVCL_6926
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Key Molecule: Zinc finger and BTB domain-containing protein 7A (ZBTB7A) [7]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Regorafenib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice, MHCC97-H cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In the present work, our results, for the first time, revealed that FBI-1 induced the aerobic glycolysis/Warburg effect of HCC cells by enhancing the expression of HIF-1alpha and its target genes.

Investigative Drug(s) 2 drug(s) in total

27-Hydroxycholesterol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Glucose-regulated protein 75 (GRP75) [17]

• Metabolic Type: Redox metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: 27-Hydroxycholesterol
• Molecule Alteration: Activity; activation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75).

Key Molecule: Glucose-regulated protein 75 (GRP75) [17]

• Metabolic Type: Redox metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: 27-Hydroxycholesterol
• Molecule Alteration: Activity; activation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: HepG2 cells, BALB/c nude mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75).

Cerulenin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Fatty acid synthase (FASN) [18]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Cerulenin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2/C3A cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Huh7 cells; Kidney; Homo sapiens (Human); CVCL_U442
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Importantly, our RNA sequencing analysis disclosed that the amyloid protein precursor (APP) is a crucial downstream effector of FASN in regulating CSC properties. We found that APP plays a crucial role in CSCs' characteristics that can be inhibited by cerulenin.

References

• Ref 1: Arenobufagin modulation of PCSK9-mediated cholesterol metabolism induces tumor-associated macrophages polarisation to inhibit hepatocellular carcinoma progression. Phytomedicine. 2024 Jun;128:155532.
• Ref 2: Targeting ACYP1-mediated glycolysis reverses lenvatinib resistance and restricts hepatocellular carcinoma progression. Drug Resist Updat. 2023 Jul;69:100976.
• Ref 3: Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma. Acta Pharmacol Sin. 2023 Mar;44(3):622-634.
• Ref 4: miR-23b-3p Modulating Cytoprotective Autophagy and Glutamine Addiction in Sorafenib Resistant HepG2, a Hepatocellular Carcinoma Cell Line. Genes (Basel). 2022 Aug 1;13(8):1375.
• Ref 5: URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers. Nat Commun. 2023 Oct 7;14(1):6269.
• Ref 6: Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase. Open Med (Wars). 2023 Sep 12;18(1):20230756.
• Ref 7: Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1alpha. Front Oncol. 2021 Nov 12;11:796839.
• Ref 8: ASPP2 suppresses tumour growth and stemness characteristics in HCC by inhibiting Warburg effect via WNT/beta-catenin/HK2 axis. J Cell Mol Med. 2023 Mar;27(5):659-671.
• Ref 9: Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma. Cancer Commun (Lond). 2024 Nov;44(11):1231-1260.
• Ref 10: Lactylation-Driven IGF2BP3-Mediated Serine Metabolism Reprogramming and RNA m6A-Modification Promotes Lenvatinib Resistance in HCC. Adv Sci (Weinh). 2024 Dec;11(46):e2401399.
• Ref 11: BNIP3-mediated mitophagy boosts the competitive growth of Lenvatinib-resistant cells via energy metabolism reprogramming in HCC. Cell Death Dis. 2024 Jul 5;15(7):484.
• Ref 12: Decreased lncRNA HNF4A-AS1 facilitates resistance to sorafenib-induced ferroptosis of hepatocellular carcinoma by reprogramming lipid metabolism. Theranostics. 2024 Oct 21;14(18):7088-7110.
• Ref 13: Circular RNA circUBE2D2 functions as an oncogenic factor in hepatocellular carcinoma sorafenib resistance and glycolysis. Am J Transl Res. 2021 Jun 15;13(6):6076-6086. eCollection 2021.
• Ref 14: MiR-494 induces metabolic changes through G6pc targeting and modulates sorafenib response in hepatocellular carcinoma. J Exp Clin Cancer Res. 2023 Jun 10;42(1):145.
• Ref 15: GPAT3 is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. Theranostics. 2024 Jun 1;14(9):3470-3485.
• Ref 16: Glycolysis maintains AMPK activation in sorafenib-induced Warburg effect. Mol Metab. 2023 Nov;77:101796.
• Ref 17: 27-Hydroxycholesterol is a specific factor in the neoplastic microenvironment of HCC that causes MDR via GRP75 regulation of the redox balance and metabolic reprogramming. Cell Biol Toxicol. 2022 Apr;38(2):311-324.
• Ref 18: Fatty acid synthase inhibitor cerulenin hinders liver cancer stem cell properties through FASN/APP axis as novel therapeutic strategies. J Lipid Res. 2024 Nov;65(11):100660.