Research Questions:
1.Do androgen receptor inhibitors (ARIs) improve liver function and slow fibrosis progression in prostate cancer patients with comorbid metabolic dysfunction-associated steatohepatitis (MASH)?
2.Are ARIs associated with a reduced incidence of hepatocellular carcinoma (HCC) or hepatic decompensation in this population?
3.How do metabolic profiles (BMI, diabetes, lipid levels) and ARI exposure duration influence hepatic outcomes?
Objectives:
1.To compare longitudinal liver function (ALT, AST) and fibrosis progression (FIB-4, APRI) between prostate cancer patients with MASH who receive ARIs versus those who do not.
2.To evaluate whether ARI exposure is associated with reduced risks of cirrhosis, HCC, or hepatic decompensation.
3.To explore interactions between ARIs and metabolic factors (e.g., diabetes, obesity, lipid levels, concurrent therapies) in modulating liver-related outcomes.
Scientific Rationale:
MASH is a major global cause of cirrhosis and liver transplantation, yet no approved therapies reverse fibrosis. Preclinical studies from our group demonstrate that AR blockade in murine MASH models suppresses hepatic inflammation, normalizes transaminases, attenuates fibrosis, and prevents HCC development. Enzalutamide replicated these protective effects in vivo, suggesting potential for translational benefit. Clinically, prostate cancer patients commonly present with metabolic syndrome, predisposing them to MASH. ARIs, already in widespread use with established safety profiles, may represent a repurposing opportunity to address this unmet need. However, the effect of ARIs on liver outcomes in human MASH remains unexplored. By leveraging UK Biobank’s longitudinal data, this study aims to provide the first human evidence on the hepatic impact of ARIs in this dual-disease context. Positive findings would justify future prospective trials of ARIs as antifibrotic therapy in MASH, extending therapeutic utility beyond oncology.
