The Liver-Testis Axis: Molecular Mechanisms and Clinical Implications

Metabolic dysfunction-associated steatotic liver disease (MASLD) and male hypogonadism (HG) are prevalent disorders that frequently coexist, suggesting a bidirectional "liver-testis axis" as a potential pathophysiological link. This review explores the mechanistic basis and clinical implications of this axis. Molecularly, metabolically stressed hepatocytes release an altered hepatokine signature-marked by reduced sex hormone-binding globulin (SHBG) and elevated fibroblast growth factor 21 (FGF21)-along with pro-inflammatory cytokines (e.g., interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)), which enter the systemic circulation. These factors may contribute to the impairment of Leydig cell steroidogenesis, the perturbation of blood-testis barrier integrity, and the disruption of spermatogenesis. Conversely, testicular dysfunction and subsequent testosterone deficiency promote visceral adiposity, worsen insulin resistance and amplify chronic inflammation, thereby accelerating hepatic steatosis and fibrosis. Clinically, these molecular interactions manifest as mutually worsening of MASLD and HG. Thus, the liver-testis axis establishes a framework that reveals the bidirectional crosstalk between hepatic metabolism and gonadal function, providing novel pathophysiological insights into these interconnected conditions.