Fetuin-A Attenuates HMGB1/TLR4-Mediated Ovarian Ischemia/Reperfusion Injury

Background/Objectives: Adnexal torsion causes ovarian ischemia/reperfusion injury and may impair ovarian reserve. This study evaluated the protective effects of Fetuin-A in a rat torsion/detorsion model. Methods: Twenty-eight female Wistar rats were assigned to Sham, T/D, T/D+Fetuin-A treatment, and Fetuin-A pretreatment+T/D groups. Bilateral ovarian torsion was induced for 3 h followed by 2 h of detorsion/reperfusion, and Fetuin-A was administered intraperitoneally at 100 mg/kg. Serum cytokines and AMH, qRT-PCR markers, histopathological injury, and immunohistochemical expression of Fetuin-A, HIF-1α, GPx, and Bcl-2 were evaluated. Results: T/D induced a systemic inflammatory response, reduced AMH, increased HMGB1/TLR4-associated and cell-stress markers, and caused marked ovarian histopathological injury. Fetuin-A attenuated inflammatory and molecular stress responses, while pretreatment produced the most consistent protection, preserving AMH, reducing histopathological injury and HIF-1α immunoreactivity, and restoring GPx, Bcl-2, and Fetuin-A immunoreactivity. Exploratory STRING analysis identified functional enrichment related to oxidative stress, autophagy, apoptosis, and HIF-1 signaling, providing hypothesis-generating context without establishing causal pathway activity. Conclusions: These findings indicate that Fetuin-A administration, particularly before torsion, was associated with reduced inflammatory and tissue-stress responses during early ovarian ischemia/reperfusion injury. Further studies are needed to determine optimal dosing, clinically feasible timing, and long-term reproductive outcomes.