Increased CAPG inhibits ferroptosis to drive tumor proliferation and sorafenib resistance in hepatocellular carcinoma via the WDR74-p53-SLC7A11 pathway.

Abstract

Hepatocellular carcinoma (HCC) presents a global therapeutic challenge owing to its aggressive tumor progression and limited treatment options. Therefore, identifying novel therapeutic targets is urgently needed. In this study, we identified CAPG as a top candidate gene that is upregulated in HCC tissues and predicts poor clinical prognosis, based on proteomic sequencing, public database analysis, and immunohistochemistry. The biological role of CAPG in HCC tumorigenesis was investigated using cell lines, xenograft models, and pulmonary metastasis models. We found that CAPG depletion inhibited tumor proliferation and metastasis both in vivo and in vitro. Functional assays were also performed to assess the effects of CAPG on sorafenib-induced ferroptosis. Colony formation assays, IC₅₀ assays, qPCR, and Western blot analyses were conducted to examine the relationship between CAPG expression and sorafenib treatment. Notably, CAPG was upregulated following sorafenib exposure and contributed to sorafenib resistance. RNA sequencing, ChIP sequencing, co-immunoprecipitation, and ubiquitination assays were further employed to elucidate the molecular mechanisms involving CAPG. Mechanistically, CAPG promoted gene expression by inducing WDR74 transcription, which modulated the interaction between p53 and MDM2, resulting in p53 degradation. Our findings demonstrate that CAPG drives tumor proliferation and sorafenib resistance by inhibiting ferroptosis, suggesting that CAPG may serve as a promising target in HCC.