{
 "gene": "GPX4",
 "run_date": "2026-06-10T01:55:21",
 "timeline": {
  "current_model": "GPX4 is a selenocysteine-containing lipid hydroperoxidase that reduces phospholipid hydroperoxides to non-toxic lipid alcohols using glutathione as the reducing substrate, thereby preventing iron-dependent lipid peroxidation and ferroptosis; its activity, stability, and subcellular localization are regulated at multiple levels including selenocysteine-based catalysis (superior to Cys for resisting overoxidation), alternative promoter-driven isoform expression (cytosolic, mitochondrial, nuclear), and an extensive post-translational modification network encompassing K48/K63/M1-linked ubiquitination by E3 ligases (STUB1, NEDD4L, CUL1-FBW7) and stabilization by deubiquitinases (USP8, OTUD5, OTUB1), S-palmitoylation at C66/C75 by ZDHHC20/ZDHHC8 (reversed by APT2), arginine-152 methylation by PRMT5, and serine-104 phosphorylation by CKB; direct covalent modification at C66 by itaconate allosterically activates GPX4; copper-induced ubiquitination at C107/C148 and chaperone-mediated autophagy (legumain/HSC70) or selective autophagy (TAX1BP1, TRAF6-p62) drive its degradation; transcriptional control by STAT3, KLF11, and epigenetic mechanisms (m6A via METTL3/ALKBH5/FTO, DNMT-mediated promoter methylation) modulates GPX4 levels; functionally, GPX4 is essential for TFH cell survival, innate immune STING activation (by preventing lipid peroxidation-induced STING carbonylation at C88), and host resistance to Mycobacterium tuberculosis, and in adipocytes it suppresses metabolic inflammation independently of overt ferroptosis."
 },
 "narrative": {
  "mechanism_profile": {
   "molecular_activity": [
    {
     "term_id": "GO:0016491",
     "term_label": "oxidoreductase activity",
     "supporting_discovery_ids": [
      0,
      1,
      5,
      6,
      27
     ]
    },
    {
     "term_id": "GO:0140098",
     "term_label": "catalytic activity, acting on RNA",
     "supporting_discovery_ids": [
      1,
      6,
      26
     ]
    },
    {
     "term_id": "GO:0008289",
     "term_label": "lipid binding",
     "supporting_discovery_ids": [
      8
     ]
    },
    {
     "term_id": "GO:0003677",
     "term_label": "DNA binding",
     "supporting_discovery_ids": [
      8,
      9
     ]
    },
    {
     "term_id": "GO:0016209",
     "term_label": "antioxidant activity",
     "supporting_discovery_ids": [
      0,
      1,
      28
     ]
    }
   ],
   "localization": [
    {
     "term_id": "GO:0005829",
     "term_label": "cytosol",
     "supporting_discovery_ids": [
      9,
      24
     ]
    },
    {
     "term_id": "GO:0005739",
     "term_label": "mitochondrion",
     "supporting_discovery_ids": [
      24,
      28
     ]
    },
    {
     "term_id": "GO:0005634",
     "term_label": "nucleus",
     "supporting_discovery_ids": [
      8,
      9
     ]
    },
    {
     "term_id": "GO:0005886",
     "term_label": "plasma membrane",
     "supporting_discovery_ids": [
      8
     ]
    }
   ],
   "pathway": [
    {
     "term_id": "R-HSA-5357801",
     "term_label": "Programmed Cell Death",
     "supporting_discovery_ids": [
      0,
      1,
      3
     ]
    },
    {
     "term_id": "R-HSA-8953897",
     "term_label": "Cellular responses to stimuli",
     "supporting_discovery_ids": [
      0,
      1,
      2
     ]
    },
    {
     "term_id": "R-HSA-168256",
     "term_label": "Immune System",
     "supporting_discovery_ids": [
      4,
      29,
      30
     ]
    },
    {
     "term_id": "R-HSA-392499",
     "term_label": "Metabolism of proteins",
     "supporting_discovery_ids": [
      11,
      18,
      20,
      22,
      34
     ]
    },
    {
     "term_id": "R-HSA-9612973",
     "term_label": "Autophagy",
     "supporting_discovery_ids": [
      10,
      12,
      34,
      24
     ]
    }
   ],
   "complexes": [],
   "partners": [
    "STING",
    "CKB",
    "PRMT5",
    "ZDHHC20",
    "USP8",
    "OTUD5",
    "STUB1",
    "TRAF6"
   ],
   "other_free_text": []
  }
 },
 "prefetch_data": {
  "uniprot": {
   "accession": "P36969",
   "full_name": "Phospholipid hydroperoxide glutathione peroxidase GPX4"
  }
 },
 "evaluation": {
  "pairwise": "win",
  "faith_supported": 7,
  "faith_total": 7,
  "faith_pct": 100.0
 },
 "cost": {
  "total_usd": 0.298839
 }
}