Metabolic and Hepatic Effects of Androgen Receptor Downregulation by PROTAC ARV-110 in a Mouse Model of Polycystic Ovary Syndrome

Background: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, with hyperandrogenism being a hallmark feature strongly associated with metabolic dysfunction. Androgens exert their biological effects through the androgen receptor (AR), driving downstream transcriptional activity. Targeting the AR may alleviate PCOS complications: however, the use of AR blockers is discouraged due to their severe hepatotoxic effects, highlighting the need for safer therapeutic options. ARV-110, a novel AR Proteolysis Targeting Chimera (PROTAC) degrader, has shown high efficacy to abolish AR-mediated effects in prostate cancer; however, its safety and efficacy in PCOS are unknown. Therefore, we hypothesized that the AR degrader ARV-110 will dose-dependently mitigate androgen excess-mediated metabolic dysfunction while avoiding hepatotoxicity in a well-established hyperandrogenemic mouse model of PCOS. Methods: Three-week old female mice (C57BL/6N) were implanted with Silastic tubes with the androgen dihydrotestosterone (DHT, 8mg, s.c., 90 days) or control (CON) (n=6/grp). Four weeks post-DHT administration, mice were treated with ARV-110 at either a low-dose (ARV-L, 1 mg/kg/day, s.c.) or a high-dose (ARV-H, 10 mg/kg/day, s.c.) or vehicle (VEH) for an additional 8 weeks. Body weight (BW), liver weight, body composition by EchoMRI, fasting glucose (FG), and oral glucose tolerance test (OGTT) were assessed. Circulating liver injury markers (AST, ALT, and LDH) were measured in the serum. Hepatic steatosis was assessed in PicroSirius Red-stained liver sections. Liver discovery proteomics were analyzed using VolcaNoseR, BioVenn, and canonical pathway enrichment with Ingenuity Pathway Analysis. Data were analyzed by 2-way ANOVA using GraphPad prism. Results: DHT-VEH mice exhibited significant (p<0.05) increases in BW (27.3±0.6 vs 23.9±0.2 g), fat mass (4.2±0.6 vs 2.1±0.1 g), lean mass (21.6±0.2 vs 19.8±0.2 g), FG (183.2±25.2 vs 141.5±9.9 mg/dL), and impaired glucose tolerance (OGTT, AUC:34557±6255 vs 23459±1896 mg.min/dL) compared to CON-VEH mice. Both ARV-L and ARV-H treatments in DHT mice significantly reduced BW, fat mass, FG and OGTT without impacting lean mass. However, while ARV-L had no effect on the DHT-induced increase in liver weight, ARV-H further increased it. Similarly, ALT, AST, and LDH levels were comparable between VEH- and ARV-L-treated mice, but ARV-H significantly elevated these markers, suggesting hepatotoxicity. Additionally, ARV-L significantly reduced hepatic steatosis compared to DHT-VEH mice, whereas ARV-H had the opposite effect. Discovery proteomics analysis of the liver identified 217 differentially expressed proteins (DEPs) in DHT-VEH mice compared to CON-VEH mice. In comparison to DHT-VEH mice, ARV-L treatment resulted in 76 DEPs, while ARV-H led to a substantially higher number of 681 DEPs. Furthermore, pathway enrichment analysis showed that only ARV-H treatment activated pathways associated with autophagy, apoptosis, OXPHOS, inflammatory, and TNFR2 & NIK mediated non-canonical NF-ĸB signaling, indicating liver dysregulation. Conclusion and significance: Our findings show that DHT-induced obesity (increased BW and fat mass) and glucose intolerance (increased FG and impaired OGTT) are ameliorated by both ARV-L and ARV-H treatments. However, liver injury markers and proteomic analysis indicate that while ARV-L has minimal effects on the liver, ARV-H treatment induces severe hepatotoxicity. These results highlight the potential of AR PROTACs as a novel therapeutic approach for managing metabolic complications in PCOS, provided the dosing is carefully optimized to avoid adverse effects. Supported by NIH NIGMS grants P20GM121334 (L.L.Y.C., S.R. and D.G.R.), R01HL144847 (D.G.R.), and AHA Predoctoral Fellowships 24PRE1200831 (J.B.) and 903804 (A.M.H.). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.