Protective effect of pirfenidone against ovarian ischemia/reperfusion injury in rats via modulation of TLR4/p38 MAPK/IL-1β and HIF-1α/VEGF-A signaling pathways

Abstract Objective Ovarian ischemia/reperfusion (I/R) injury is a common gynecological emergency, typically caused by ovarian torsion. Pirfenidone (PFN) has demonstrated potential therapeutic benefits due to its antioxidant, anti-inflammatory, and antiapoptotic properties. This research aimed to investigate the protective effects of PFN in alleviating ovarian I/R injury in female rats. Methods Female rats received PFN (300 mg/kg/day) for 3 consecutive days, either with or without the induction of ovarian I/R. The study assessed markers of ovarian oxidative stress, inflammation, apoptosis, and the levels of hypoxia-inducible factor-1 alpha and vascular endothelial growth factor-A (VEGF-A). Ovarian histology was analyzed, along with immunohistochemical staining for Toll-like receptor 4 (TLR4) and p38 mitogen-activated protein kinase (p38 MAPK). Key findings I/R injury resulted in increased oxidative stress, inflammation, apoptosis, and a significant reduction in ovarian VEGF-A levels. Histological examination revealed ovarian damage, with increased expression of TLR4 and p38 MAPK. PFN treatment significantly improved the hormonal balance and mitigated oxidative stress, inflammatory, and apoptotic markers to normal levels. In addition, PFN improved ovarian tissue morphology and decreased TLR4 and p38 MAPK expression. Conclusions The findings suggest that PFN may offer protective effects against ovarian I/R injury through its antioxidant, anti-inflammatory, and antiapoptotic properties, as well as by promoting angiogenesis in the ovary.