Androgen receptor signaling in hepatocellular carcinoma: mechanisms of male predominance and therapeutic opportunities.

Hepatocellular carcinoma (HCC) is two to four times more common in men than in women. The sex distribution of viral hepatitis, alcohol use and adiposity explains only part of this difference, which points to sex-specific host biology as a further driver. The androgen receptor (AR), a ligand-activated transcription factor expressed in hepatocytes and in most HCC, is a strong candidate: both epidemiologic and experimental data implicate it in the male excess. This review draws that evidence together. Prospective cohorts link higher circulating testosterone and sex hormone-binding globulin to liver cancer risk, although raising SHBG experimentally suppresses rather than promotes hepatocarcinogenesis, a discordance that bears on how those associations should be read, and experimental studies group the underlying biology into several modules: constitutively active AR and its splice variants, kinase-driven phosphorylation of the receptor, downstream effectors of proliferation, invasion and angiogenesis, non-coding RNA circuits, androgen-metabolizing enzymes and the systemic endocrine axis, and the effect of androgen on the tumor immune microenvironment. The weight of each module differs across hepatitis B virus (HBV)-related, hepatitis C virus (HCV)-related, metabolic dysfunction-associated and anabolic steroid-induced disease. Therapeutic work remains largely preclinical and has centered on AR antagonists combined with tyrosine kinase inhibitors or immune checkpoint blockade, on degraders aimed at AR splice variants, on proteolysis-targeting chimeras and nucleic-acid approaches that eliminate ligand-independent receptor states, and on enzyme inhibitors. Two problems still limit translation: AR appears oncogenic in most settings but tumor-suppressive in some, and androgen suppresses antitumor immunity in certain contexts while enhancing it in others. Clarifying when each holds is what will determine whether AR-directed therapy, already established in prostate cancer, can be extended to liver cancer.