CAPRIN1-mediated sequestration of NCOA4 mRNA into stress granules drives sorafenib resistance in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with therapeutic resistance posing a critical barrier to improving patient outcomes. While stress granules (SGs) are implicated in tumor adaptation, their molecular features, clinical relevance, and mechanistic roles in HCC remain poorly defined. Here, we established a 26-gene SG signature and develop a SG score that robustly stratifies HCC patients, linking high score with aggressive molecular subtypes and poor survival. Moreover, we demonstrate that β-catenin directly binds the promoters of SG genes and activates their transcription. Crucially, we reveal that elevated SG activity correlates sorafenib resistance and identify CAPRIN1 as a key driver of sorafenib resistance through suppression of ferroptosis. Mechanistically, CAPRIN1 interacts with NCOA4 mRNA via its RGG domain and recruits NCOA4 mRNA into SGs, leading to repression of NCOA4 translation and consequent blunting of sorafenib-induced ferroptosis. Genetic disruption of CAPRIN1 restores NCOA4 expression and resensitizes resistant tumors to sorafenib. Our work establishes SG activity as a prognostic biomarker and reveals a druggable SG-ferroptosis axis, offering novel strategies to overcome therapy resistance in HCC.