E3 ligase SMURF2 alleviated intrauterine adhesion by stabilizing SMAD6

Abstract

Intrauterine adhesion (IUA) is a debilitating uterine disorder characterized by endometrial fibrosis and infertility, for which effective treatments remain limited. Here, we identify the E3 ubiquitin ligase SMURF2 as a critical protective factor against IUA progression. SMURF2 expression was significantly upregulated in endometrial tissues of IUA patients, a murine IUA model, and TGF-β1-treated human endometrial stromal cells (HESCs). Functional analyses revealed that SMURF2 overexpression mitigated fibrosis-associated phenotypes, including enhanced cell proliferation, migration, and extracellular matrix accumulation, both in vitro and in vivo, whereas SMURF2 knockdown had the opposite effect. Mechanistically, SMURF2 directly interacted with the inhibitory SMAD protein SMAD6 and promoted its stabilization via K63-linked polyubiquitination. Mutation analysis confirmed that disruption of the K63 linkage markedly reduced SMAD6 ubiquitination and destabilized the protein. As a result, SMAD6 accumulation suppressed TGF-β/Smad signaling and downstream fibrotic gene expression. These findings reveal a previously unrecognized SMURF2–SMAD6 axis that counteracts endometrial fibrosis, and suggest that enhancing SMURF2-mediated K63-linked ubiquitination may offer a novel therapeutic avenue for IUA treatment.