Simvastatin overcomes the pPCK1‐pLDHA‐SPRINGlac axis‐mediated ferroptosis and chemo‐immunotherapy resistance in AKT‐hyperactivated intrahepatic cholangiocarcinoma

Abstract Background Intrahepatic cholangiocarcinoma (ICC) is a challenging cancer with an increasing incidence. The Phase III TOPAZ‐1/KEYNOTE‐966 study demonstrated chemo‐immunotherapy (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. Methods In vivo metabolic CRISPR screening in a Kras G12D /Tp53 −/− ICC mouse model was used to identify primary regulators of ferroptosis during CIT (gemcitabine, cisplatin, and anti‐mouse 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‐related resistance mechanisms in AKT‐hyperactivated ICC. Results Under AKT hyperactivation condition, phosphorylated PCK1 (pPCK1) promoted metabolic reprogramming, enhancing ubiquinol and menaquinone‐4 synthesis through the mevalonate (MVA) pathway. This cascade was mediated by the pPCK1‐pLDHA‐SPRINGlac axis. Inhibiting PCK1 phosphorylation or using simvastatin significantly augmented CIT efficacy in preclinical models. Clinical data further indicated that phosphorylated AKT (pAKT)‐pPCK1 levels might serve as a biomarker to predict CIT response in ICC. Conclusion This study identified the pAKT‐pPCK1‐pLDHA‐SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT‐hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin‐based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.