biostudies-literatureWang HNational Natural Science Foundation of China148https://www.ebi.ac.uk/biostudies/studies/S-EPMC12574091biostudies-literatureUnknown15(1)<h4>Background</h4>Males and females exhibit pronounced disparity in the epidemiology, clinical progression, and therapeutic outcomes of colonic diseases, but the underlying mechanisms that regulate sexual dimorphism of colon remain poorly understood.<h4>Results</h4>We determined the colon as a pivotal androgen metabolic hub, where gonad-derived androgens drive sex-dimorphic levels, while androgen-metabolizing enzymes maintain androgen homeostasis in colon. We identified IL-33⁺ colonic stromal cells as the dominant AR-expressing population in colon. Mechanistically, sex-biased androgen levels govern the nuclear translocation of androgen receptor and further assembly of AR liquid-liquid phase-separated condensates in the immunomodulatory stromal cells of male colon. Notably, we uncovered AR-directed transcriptional programs via nuclear AR phase separation underlying sex-biased expression of key factors, including SerpinA3N and MT1, thereby defining molecular base for sex disparities through gonad-colon axis.<h4>Conclusion</h4>These findings provide molecular and cellular base for sex disparities through an androgen-IL33⁺ stromal cell axis in colon.Cell & bioscienceSexual dimorphism in colon is mediated by an androgen-IL33&lt;sup&gt;+&lt;/sup&gt; stromal cell axis.PMC1257409132370655Lan TZou JZhou RHu MWang HJing BLin LCheng HfalseSexual dimorphism in colon is mediated by an androgen-IL33&lt;sup&gt;+&lt;/sup&gt; stromal cell axis.<h4>Background</h4>Males and females exhibit pronounced disparity in the epidemiology, clinical progression, and therapeutic outcomes of colonic diseases, but the underlying mechanisms that regulate sexual dimorphism of colon remain poorly understood.<h4>Results</h4>We determined the colon as a pivotal androgen metabolic hub, where gonad-derived androgens drive sex-dimorphic levels, while androgen-metabolizing enzymes maintain androgen homeostasis in colon. We identified IL-33⁺ colonic stromal cells as the dominant AR-expressing population in colon. Mechanistically, sex-biased androgen levels govern the nuclear translocation of androgen receptor and further assembly of AR liquid-liquid phase-separated condensates in the immunomodulatory stromal cells of male colon. Notably, we uncovered AR-directed transcriptional programs via nuclear AR phase separation underlying sex-biased expression of key factors, including SerpinA3N and MT1, thereby defining molecular base for sex disparities through gonad-colon axis.<h4>Conclusion</h4>These findings provide molecular and cellular base for sex disparities through an androgen-IL33⁺ stromal cell axis in colon.2025-01-01T00:00:00Z2025 Oct2026-06-05T08:55:00.894Z2026-05-14T03:13:07.762ZS-EPMC125740914116307910.1186/s13578-025-01493-9