Current status and perspectives of molecular mechanisms of gender difference in hepatocellular carcinoma: The tip of the iceberg?

Hepatocellular carcinoma (HCC) risk factors and incidence vary globally, but men generally have higher incidence than women. Men also tend to have a worse prognosis in terms of survival period and pathological characteristics. Furthermore, there are notable gender differences in treatment strategies and drug responses. While traditional risk factors such as hepatitis B virus, hepatitis C virus, alcohol consumption, and metabolic syndrome contribute to these differences, the underlying molecular mechanisms remain partly understood. Recent research has focused on elucidating the roles of sex hormones, DNA damage and repair pathways, immune microenvironments, and genetic/epigenetic factors in driving gender-specific disparities. For instance, estrogen receptor signaling has been shown to suppress HCC progression, whereas androgen receptor signaling promotes tumor development. Additionally, immune cells such as tumor-associated macrophages and regulatory T cells exhibit gender-specific patterns, with males typically showing higher levels of immunosuppressive cells. Omics analyses, including genomics, transcriptomics, and proteomics, have further revealed sex-specific differences in gene expression, protein interactions, and metabolic pathways. Despite these advances, significant gaps remain in understanding the interplay between environmental, hormonal, and genetic factors in shaping gender disparities in HCC. Future research should prioritize the identification of novel molecular targets, the development of gender-specific therapeutic strategies, and the integration of multi-omics data to address these disparities. Addressing these challenges will be critical for improving diagnostic, prognostic, and therapeutic outcomes in HCC patients of both sexes.