2. Academic Validation
  3. Simvastatin overcomes the pPCK1-pLDHA-SPRINGlac axis-mediated ferroptosis and chemo-immunotherapy resistance in AKT-hyperactivated intrahepatic cholangiocarcinoma

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

  • Cancer Commun (Lond). 2025 May 29. doi: 10.1002/cac2.70036.
Jinghan Zhu 1 2,  Yixiao Xiong 1 2 3,  Yuxin Zhang 1 2 4,  Huifang Liang 1 2 5,  Kun Cheng 1 2,  Yuanxiang Lu 1 2,  Guangzhen Cai 1 2,  Yang Wu 1 2,  Yunhui Fan 1 2,  Xiaoping Chen 1 2 5,  Hong Zhu 6,  Zeyang Ding 1 2 5,  Wanguang Zhang 1 2 5
Affiliations

Affiliations

  • 1 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
  • 2 Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei, P. R. China.
  • 3 Department of Dermatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
  • 4 Department of Gynecological Oncology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
  • 5 Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei, P. R. China.
  • 6 Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P. R. China.
PMID: 40443016 DOI: 10.1002/cac2.70036
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 KrasG12D/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.

Keywords

Chemo‐immunotherapy; Ferroptosis; Intrahepatic cholangiocarcinoma; Lactylation; Mevalonate pathway; PCK1.

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