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The Phase III TOPAZ\u20101\/KEYNOTE\u2010966 study demonstrated chemo\u2010immunotherapy (CIT) as a significant advancement, potentially replacing traditional chemotherapy for advanced biliary tract cancer. Ferroptosis is a crucial process that affects cancer cell survival and therapy resistance. Although AKT hyperactivation is prevalent in numerous cancers, including ICC, its role in ferroptosis resistance remains unclear. This study explored whether targeting ferroptosis can enhance CIT response rates, specifically in ICC patients with AKT hyperactivation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      In vivo metabolic CRISPR screening in a Kras\n                      <jats:sup>G12D<\/jats:sup>\n                      \/Tp53\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      ICC mouse model was used to identify primary regulators of ferroptosis during CIT (gemcitabine, cisplatin, and anti\u2010mouse programmed cell death 1 ligand 1). Phosphoenolpyruvate carboxykinase 1 (PCK1) was assessed for its role in ferroptosis and treatment resistance in preclinical models under AKT activation levels. Molecular and biochemical techniques were used to explore PCK1\u2010related resistance mechanisms in AKT\u2010hyperactivated ICC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">Under AKT hyperactivation condition, phosphorylated PCK1 (pPCK1) promoted metabolic reprogramming, enhancing ubiquinol and menaquinone\u20104 synthesis through the mevalonate (MVA) pathway. This cascade was mediated by the pPCK1\u2010pLDHA\u2010SPRINGlac axis. Inhibiting PCK1 phosphorylation or using simvastatin significantly augmented CIT efficacy in preclinical models. Clinical data further indicated that phosphorylated AKT (pAKT)\u2010pPCK1 levels might serve as a biomarker to predict CIT response in ICC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p xml:lang=\"en\">This study identified the pAKT\u2010pPCK1\u2010pLDHA\u2010SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT\u2010hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin\u2010based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.70036","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T01:20:37Z","timestamp":1748568037000},"page":"1038-1071","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Simvastatin overcomes the pPCK1\u2010pLDHA\u2010SPRINGlac axis\u2010mediated ferroptosis and chemo\u2010immunotherapy resistance in AKT\u2010hyperactivated intrahepatic cholangiocarcinoma"],"prefix":"10.34133","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6310-1672","authenticated-orcid":false,"given":"Jinghan","family":"Zhu","sequence":"first","affiliation":[{"name":"Tongji Hospital","place":["Wuhan, P. R. China"]},{"name":"Tongji Medical College","place":["Wuhan, P. R. 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