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 r

SUBMITTER: Zhu J 

PROVIDER: S-EPMC12365544 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature