Molecule Information

General Information of the Molecule (ID: Mol02212)

• Name: Long non-protein coding RNA (HNF4A-AS1) ,Homo sapiens
• Synonyms: HNF4A-AS1
• Molecule Type: LncRNA
• Gene Name: HNF4A-AS1

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Acetaminophen

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [1]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Resistant Drug: Acetaminophen
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepaRG cells; Liver; Homo sapiens (Human); CVCL_9720
• Experiment for Molecule Alteration: Knockdown assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Altogether, our study suggests that HNF1alpha-AS1 and HNF4alpha-AS1 affected AILI mainly through alterations of P450-mediated APAP biotransformation in HepaRG cells, indicating an important role of the LncRNAs in AILI.

Regorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [2]

• 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.

Sorafenib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [3]

• Resistant Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• 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: MHCC97H cells; Liver; Homo sapiens (Human); CVCL_4972
• In Vitro Model: SNU449 cells; Liver; Homo sapiens (Human); CVCL_0454
• In Vitro Model: Huh7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: MIHA cells; Liver; Homo sapiens (Human); CVCL_SA11
• In Vivo Model: BALB/c nude mice model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western blot assay; RNA immunoprecipitation assay
• Experiment for Drug Resistance: Xenograft assay; Cell cytotoxicity assay; Cell viability assay
• Mechanism Description: Bioinformatics analysis revealed that HNF4A-AS1, a lipid metabolism-related lncRNA, is specifically high-expressed in the normal liver and associated with sorafenib resistance in HCC. We further confirmed that HNF4A-AS1 was downregulated in HCC cells and organoids that resistant to sorafenib. Moreover, both in vitro and in vivo studies demonstrated that HNF4A-AS1 overexpression reversed sorafenib resistance in HCC cells, which was further enhanced by polyunsaturated fatty acids (PUFA) supplementation. 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.

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [2]

• 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.

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [2]

• 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.

References

• Ref 1: Knockdown of Long Noncoding RNAs Hepatocyte Nuclear Factor 1Alpha Antisense RNA 1 and Hepatocyte Nuclear Factor 4Alpha Antisense RNA 1 Alters Susceptibility of Acetaminophen-Induced Cytotoxicity in HepaRG CellsMol Pharmacol. 2020 Apr;97(4):278-286. doi: 10.1124/mol.119.118778. Epub 2020 Feb 6.
• Ref 2: 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 3: 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.