CAPG Regulates Doxorubicin Resistance in Hepatocellular Carcinoma Cells via TGFB1/Smad/Nrf2 Signalling Pathway

Hepatocellular carcinoma (HCC) is a common and deadly type of liver cancer with limited treatment options and a considerable issue with chemoresistance. This study investigates the role of the cytoskeleton-associated protein G (CAPG) gene in HCC and explores its expression, clinical relevance, as well as the molecular mechanisms on doxorubicin (Dox) resistance. Employing bioinformatics, immunohistochemistry, cell-based assays and animal models, we systematically explored CAPG's function in HCC. Our results demonstrated that CAPG was markedly upregulated in HCC tissues and cell lines compared to normal controls (***p < 0.001). High CAPG expression was associated with poor overall survival (HR = 1.98, p < 0.001) and unfavourable clinicopathological parameters, indicating its potential as a prognostic biomarker. Functional experiments indicated that CAPG knockdown significantly reduced viability and proliferation in Dox-resistant HCC cells (***p < 0.01). Conversely, overexpression promoted resistance. Mechanistically, CAPG appears to modulate ferroptosis via the TGFB1/Smad2/NRF2 signalling pathway, as supported by GSEA analysis and subsequent molecular assays. In vivo, CAPG knockdown in combination with Dox treatment significantly inhibited tumour growth in nude mouse models (***p < 0.01). These findings suggest that CAPG is a pivotal regulator of HCC progression and chemoresistance, offering a promising prognostic biomarker and combinatorial therapeutic target to overcome Dox resistance in clinical settings.