HMGB1-enhanced autophagic degradation of E-cadherin facilitates mesothelial trans-differentiation and postoperative peritoneal adhesion.

Postoperative peritoneal adhesion (PA), a prevalent complication of abdominal surgery, arises from aberrant healing of the injured peritoneum. This process involves mesothelial cell trans-differentiation into myofibroblast-like cells, driving peritoneal matrix remodeling and pathological fibrous band formation between organs. Existing therapeutic strategies to prevent PA exhibit limited efficacy, underscoring the need for previously unrecognized mechanistic insights into PA pathogenesis. Here, we elucidate the role of autophagy in mesothelial cell transition and PA development. Utilizing a murine PA model coupled with comprehensive in vitro analyses, we demonstrate that HMGB1-mediated autophagy facilitates TGF-β mediated mesothelial cell trans-differentiation. Specifically, autophagic degradation of E-cadherin counteracts TGF-β-driven mesothelial transition. Pharmacological activation of autophagy via rapamycin or recombinant HMGB1 potentiated this transition, whereas HMGB1 inhibitor (glycyrrhizin) or autophagy suppressor (spautin-1) markedly attenuated it. Crucially, early postoperative administration of glycyrrhizin or spautin-1 significantly reduced PA severity. Our findings unveil autophagy and HMGB1 as pivotal regulator targets of mesothelial plasticity during PA formation, provide mechanistic insights into peritoneum repair, and propose novel therapeutic avenues for PA prevention.