ABSTRACT Rates of cirrhosis from nonalcoholic steatohepatitis (NASH) are rapidly rising in young adults, and given limited therapies and the heterogeneity of affected individuals, there is an urgent and unmet need to identify tailored therapeutic targets for at-risk young populations. Androgens may reflect such target for the 10-15%, or nearly 10 million reproductive-aged women with Polycystic Ovary Syndrome (PCOS). PCOS is typically marked by elevated androgens, and over 50% of these women have NAFLD. We have shown PCOS to increase the risk of prevalent NASH and advanced NASH fibrosis, which occurs at a younger age than in non-PCOS controls. High androgens may explain their observed “head start” in disease severity, as our cross-sectional data from young women without PCOS found higher (though normal range) testosterone levels to be associated with NASH fibrosis. Whether elevated androgens underlie the risk of liver injury in PCOS, and the potential mechanistic pathways by which this occurs, are not known. Our findings would support androgen receptor antagonism as a potential therapeutic target for the large population of women with PCOS and liver disease. Our central hypothesis is that androgens promote liver injury and NASH progression in PCOS, which occurs through aberrant lipid activity (including lipotoxicity and dysregulated de novo lipogenesis), in part from androgenic effects on visceral fat. Exogenous androgen use in women does increase visceral fat, which in turn promotes NASH through several pathways, including production of lipotoxic lipid species. Androgens are also linked to dysregulated branched-chain amino acid metabolism in PCOS, which is relevant as co-investigators on our team have discovered an enzymatic imbalance that leads to dysregulated hepatic de novo lipogenesis and NASH, and is reflected by serum levels of branched-chain amino and ketoacids. Building upon these data, we propose a 2-center (UCSF and Duke) longitudinal study of 150 reproductive- aged women with NASH (125 PCOS and 25 non-PCOS controls) to determine the influence of androgens on liver injury and progression in PCOS and the mechanistic contributions of visceral adiposity (Aim 1) and aberrant lipid metabolism (Aim 2) to this process. Aim 3 is a mechanistic proof-of-concept trial of 50 PCOS participants to determine whether 24 weeks of androgen receptor blockade improves lipid metabolites that reflect hepatic lipotoxicity and dysregulated de novo lipogenesis, respectively, as well as imaging-quantified hepatic and visceral fat, and NASH histology. Leveraging our existing UCSF PCOS cohort and the established infrastructures and collaborations between UCSF and Duke in NAFLD, PCOS, obesity, and lipid metabolism, we are well positioned to accomplish the proposed aims. Impact of findings: Determining the contribution of androgens to liver injury in PCOS and the underlying mechanistic pathways will support efficacy studies evaluating androgen receptor antagonism fo...