Naringenin ameliorates progression of endometriosis by modulating Nrf2/Keap1/ HO1 axis and inducing apoptosis in rats

Abstract Endometriosis is mainly characterized by the presence of endometrial tissue exterior to the uterus, however the exact pathophysiology of this disease still remains uncertain. Moreover, the incidence significantly contributes to infertility among women and hence, a novel treatment for endometriosis is widely investigated. Naringenin is a plant-derived flavonoid having anti-proliferative, anti-inflammatory, and anti-angiogenic properties in chronic and metabolic diseases. The study was planned with an objective to demonstrate the anti-endometriotic therapeutic potential of naringenin in rats and to examine its impact on various cellular aspects with a view to define the mechanism involved. The endometrial implant volumes, weight, TNF-α level in serum and the histopathologic scores were significantly reduced in the naringenin treated group as compared to the endometriotic control group. Naringenin ameliorated the expression of prognostic markers (TAK1, PAK1, VEGF and PCNA) involved in development and progression of endometriotic cells. Naringenin caused dose-dependent loss of mitochondrial membrane potential, induced apoptosis and inhibited proliferation in these cells. Further, a significant increase in level of Nrf2 and its downstream molecules (NQO1, HO-1) was found in endometriotic lesion, with a subsequent decrease in its repressor molecule Keap-1. Naringenin significantly modulated the expression of Nrf2 and its effector molecules downstream. It also inhibited the invasion of endometrial cells by inhibiting the expression of MMP-2 and MMP-9 in in-vitro primary culture. We conclude that naringenin may have a therapeutic potential in the treatment of endometriosis via induction of ROS-mediated apoptosis and its anti-invasive effects.