Demethylase ALKBH5 inhibits proliferation and promotes apoptosis of hepatocellular carcinoma cells by decreasing methylation levels and regulating SOCS3/STAT3 signaling

In this study, we investigated the role of ALKBH5 in the pathogenesis of hepatocellular carcinoma (HCC), focusing on the underlying molecular mechanisms. Comparative analysis of ALKBH5 expression profiles between hepatocellular carcinoma (HCC) tissues and adjacent non-tumorous liver tissues revealed a significant downregulation of ALKBH5 in malignant tissues. To investigate the functional significance of ALKBH5 in HCC pathogenesis, we employed both gain-of-function and loss-of-function approaches in HCC cell lines, utilizing overexpression and RNA interference strategies. Clinical correlation studies demonstrated that decreased ALKBH5 expression levels were significantly associated with reduced overall survival rates in HCC patients, suggesting its potential role as a prognostic biomarker. Furthermore, upregulation of ALKBH5 expression inhibited HCC cell proliferation and induced apoptosis. Through mechanistic studies, we identified SOCS3 as a downstream target of ALKBH5, which negatively regulates the STAT3 signaling pathway. In conclusion, our findings suggest that ALKBH5, as a demethylase, suppresses HCC cell proliferation and promotes apoptosis by reducing methylation levels and modulating the SOCS3/STAT3 pathway. These insights deepen our understanding of the molecular mechanisms underlying HCC and provide potential avenues for future therapeutic development.