Intraperitoneal Fetuin-A Modulates HMGB1-Associated Inflammatory Remodeling in Experimental Endometriosis

Background/Objectives: Endometriosis is a chronic inflammatory disorder characterized by ectopic endometrial-like lesions, inflammatory activation, angiogenesis, and tissue remodeling. Fetuin-A has been implicated in inflammatory regulation; however, its effects on HMGB1 mRNA expression and lesion-remodeling markers in endometriosis remain unclear. This study investigated whether intraperitoneal Fetuin-A is associated with changes in systemic inflammation and lesion-associated remodeling in a surgically induced rat model of endometriosis. Methods: After confirmation of viable endometriotic implants, female Wistar albino rats received intraperitoneal Fetuin-A or saline. Serum IL-1β, IL-6, TNF-α, and AMH levels were measured. Endometriotic implants were evaluated by qRT-PCR for HMGB1 and OPN mRNA expression and by immunohistochemistry for Fetuin-A, p62/SQSTM1, caspase-3, VEGF, OPN, and SOD1. Results: For the primary lesion-area endpoint, Fetuin-A treatment remained associated with significantly lower post-treatment lesion area after adjustment for baseline lesion area. Compared with saline, Fetuin-A treatment significantly reduced serum IL-1β, IL-6, and TNF-α concentrations and was associated with lower AMH levels. In endometriotic implants, Fetuin-A was associated with marked downregulation of HMGB1 mRNA expression, whereas OPN mRNA was modestly increased. Immunohistochemistry showed increased Fetuin-A, p62/SQSTM1, caspase-3, and SOD1 staining, together with reduced VEGF and OPN staining after Fetuin-A treatment. Conclusions: Intraperitoneal Fetuin-A attenuated experimental endometriosis, with a significant baseline-adjusted reduction in the primary lesion-area endpoint, systemic inflammatory suppression, and reduced HMGB1 mRNA expression, accompanied by changes in angiogenesis-, oxidative stress-, apoptosis-, autophagy-, and remodeling-associated markers. Because HMGB1 protein/release, RAGE/TLR4/NF-κB signaling, and specific fibrosis markers were not assessed, these findings should not be interpreted as direct HMGB1 pathway inhibition or definitive anti-fibrotic activity. Overall, these results support further mechanistic studies evaluating Fetuin-A as a potential modulator of inflammatory and lesion-remodeling processes in endometriosis.