Molecular mechanisms of sex hormones in Hepatocellular Carcinoma: a systematic review.

Sex hormones have a prominent role in the gender disparity that is apparent in hepatocellular carcinoma (HCC). This systematic review investigates the molecular mechanisms of sex hormones-androgens, estrogens, and testosterone-in HCC, addressing the gender disparities observed in HCC prevalence and progression. Relevant search terms were used to retrieve pertinent studies found in PubMed, Web of Science, and Scopus which investigated the molecular mechanism of sex hormones in developing HCC. A quality assessment using a tailored checklist was performed. This study is registered with PROSPERO (CRD42025635841). Out of the 3,076 retrieved articles, 34 met the inclusion criteria, with six focusing on androgens, fifteen on estrogens, and thirteen examining multiple sex hormones. Studies utilized in vitro and in vivo models to understand the complex interplay between sex hormones and HCC. Estrogens were found to exert protective effects through anti-inflammatory, anti-proliferative, and mitochondrial integrity mechanisms, while androgens promoted tumorigenesis via cell cycle regulation and immune checkpoint modulation. The review highlights the contrasting roles of estrogens and androgens, emphasizing the necessity for a thorough understanding of their molecular interactions and signaling pathways, such as JAK-STAT, Wnt/β-catenin, and PI3K-AKT. This review underscores the potential for sex hormone pathway targeting in HCC therapy. Further research is warranted to explore therapeutic interventions, such as estrogen receptor antagonists and androgen receptor modulators, and to address gaps in understanding hormonal influences on HCC progression.