Proanthocyanidins alleviate ovarian ischemia reperfusion injury by inhibiting ferroptosis through the SIRT1/Nrf2/GPX4 pathway.

Abstract

Ovarian ischemia reperfusion injury (IRI) is a dangerous gynecological disorder caused by ovarian torsion from the ovarian mass and surgical manipulation. To improve patient outcomes, it is necessary to explore more effective therapeutic approaches as well as their underlying mechanisms. Proanthocyanidins (PA) are polyphenolic compounds commonly present in fruits, seeds, peels of plants, and leaves. Several studies have demonstrated that PA can alleviate IRI in the liver, intestines, heart, brain, and kidneys. In the ovarian IRI, PA's exact molecular mechanisms have not yet been identified. For the purpose of elucidating PA's role and its mechanisms in the ovarian IRI, rat models of the ovarian IRI were used. Ovarian pathological changes and ferroptosis-related parameters were analyzed. Further mechanistic insights were obtained through glutathione peroxidase 4 (GPX4) inhibitor, ferroptosis inhibitor, nuclear factor E2 related factor 2 (Nrf2) agonist, Nrf2 inhibitor, sirtuin-1 (SIRT1) agonist, SIRT1 inhibitor, network pharmacology, and Western blot. Our results revealed that ferroptosis was involved in the ovarian IRI. PA pretreatment effectively alleviated IRI-induced ovarian damage, improved ovarian reserve, reduced oxidative stress, and recovered ferroptosis-related proteins in rats. Network pharmacology analysis suggested that PA may target SIRT1 and Nrf2 in ovarian IRI. SIRT1/Nrf2 signaling protected against GPX4-dependent ferroptosis in ovarian IRI. Inhibition of SIRT1/Nrf2 signaling negated PA's anti-ferroptosis effects on ovarian IRI. Overall, these findings validate that PA alleviates ovarian IRI and preserves ovarian reserve by inhibiting ferroptosis through the SIRT1/Nrf2/GPX4 pathway. These findings offer new insight into PA's protective mechanisms against ovarian IRI, supporting its potential as a therapeutic agent.