Molecule Information

General Information of the Molecule (ID: Mol04111)

• Name: Glutathione peroxidase 4 (GPX4) ,Homo sapiens
• Synonyms: Glutathione peroxidase 4
• Molecule Type: Protein
• Gene Name: GPX4
• Gene ID: 2879
• Location: chr19:1103982-1106791[+]
• Sequence:
  MSLGRLCRLLKPALLCGALAAPGLAGTMCASRDDWRCARSMHEFSAKDIDGHMVNLDKYR
  GFVCIVTNVASQUGKTEVNYTQLVDLHARYAECGLRILAFPCNQFGKQEPGSNEEIKEFA
  AGYNVKFDMFSKICVNGDDAHPLWKWMKIQPKGKGILGNAIKWNFTKFLIDKNGCVVKRY
  GPMEEPLVIEKDLPHYF
• 3D-structure: PDB ID: 7L8L; Classification: Oxidoreductase; Method: X-ray diffraction; Resolution: 1.61 Å
• Function: Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). Can also reduce cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (By similarity). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron- dependent accumulation of lipid reactive oxygen species (PubMed:24439385). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (By similarity). Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism (PubMed:11115402). Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down- regulator of the cellular 15-lipoxygenase pathway (By similarity). Can reduce fatty acid-derived hydroperoxides (PubMed:11115402, PubMed:36608588). Can also reduce small soluble hydroperoxides such as H2O2, cumene hydroperoxide and tert-butyl hydroperoxide (PubMed:17630701, PubMed:36608588). .
• Uniprot ID: GPX4_HUMAN
• Ensembl ID: ENSG00000167468
• HGNC ID: HGNC:4556

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

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Non-small cell lung carcinoma [ICD-11: 2C25.Y] [1]

• Metabolic Type: Redox metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: Etoposide
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung carcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.38E-05; Fold-change: 1.64E-01; Z-score: 4.26E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: H1688 cells; Lung; Homo sapiens (Human); CVCL_1487
• In Vitro Model: H446 cells; Lung; Homo sapiens (Human); CVCL_1562
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Furthermore, we identified E3-ubiquitin ligase NEDD4L as a major regulator of GPX4 stability. Mechanistically, Lactate increases mitochondrial ROS generation and drives activation of the p38-SGK1 pathway, which attenuates the interaction of NEDD4L with GPX4 and subsequent ubiquitination and degradation of GPX4.

Alectinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [2]

• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Resistant Drug: Alectinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: ALK1903 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: DTP cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CellTiter-Glo 3D cell viability assay
• Mechanism Description: DTP cells evade ALK-TKI-induced ROS-mediated cell death through GPX4 activity. From these data showing elevated levels of ROS that arise through decreased levels of various antioxidant factors and decreased GSH synthesis, it might be expected that ROS-mediated cell death should occur in alectinib-induced DTP cells. However, DTP cells concurrently upregulated GPX4 protein, suggesting that ALK1903 DTP cells are able to evade ROS-mediated cell death by reducing ROS level in a GPX4-dependent manner.

Rituximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [3]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Rituximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SLC7A11/GSH/GPX4 signaling pathway; Regulation; N.A.
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• Experiment for Molecule Alteration: Western blot assay; GSH assay; MDA assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Rituximab exposure induced ferroptosis in OCI-LY1 cells. However, combination with ferroptosis inhibitor ferrostatin (Fer-1) rescued ferroptosis-induced injury, indicating that ferroptosis plays a key role in rituximab-induced cell death. The SLC7A11/GSH/GPX4 signal transduction axis is the core pathway of ferroptosis, and SLC7A11 plays a major transport function in the cystine/glutamate anti-transporter (Xc-system). The extracellular cysteine is imported into the cell through the XC- system and then converted to cysteine to synthesize GSH. GPX4 uses reduced GSH as a cofactor to detoxify lipid peroxides into lipid alcohols, thereby preventing ferroptosis induced in cells.

References

• Ref 1: Drug-induced lactate confers ferroptosis resistance via p38-SGK1-NEDD4L-dependent upregulation of GPX4 in NSCLC cells. Cell Death Discov. 2023 May 15;9(1):165.
• Ref 2: Combined blockade of GPX4 and activated EGFR/HER3 bypass pathways inhibits the development of ALK-inhibitor-induced tolerant persister cells in ALK-fusion-positive lung cancer. Mol Oncol. 2025 Feb;19(2):519-539.
• Ref 3: Rituximab induces ferroptosis and RSL3 overcomes rituximab resistance in diffuse large B-cell lymphoma cells. Arch Biochem Biophys. 2024 Nov;761:110188.