Psoralen Mitigates Triptolide-Induced Ovarian Injury by Suppressing Ovarian Granulosa Cell Apoptosis Through the Activation of Nrf2 Signaling Pathway

Abstract

As a diterpenoid epoxide natural product purified from medicinal plant Tripterygium wilfordii Hook F, triptolide (TP) is extensively investigated for its significant anti-inflammatory and immunosuppressive activity. However, the application of this treatment is limited by its significant ovarian toxicity. Psoralen (Pso), a principal bioactive compound isolated from the fruits of Psoralea corylifolia L., has attracted increasing attention due to its antioxidant, anti-inflammatory, and anti-tumorigenic activities. A TP-induced ovarian injury rat model was established by administered TP intraperitoneally for 14 days. At the same time, the rats were subjected to Pso gavage intervention. At the end of treatment, histological pathology, apoptosis, mitochondrial dysfunction, and nuclear factor-erythroid 2-related factor (Nrf2) signal of ovarian tissues were detected. Moreover, the protective effects of Pso on TP-drived mitochondrial dysfunction and apoptosis in granulosa cells (GCs) were revealed in vitro. Our results indicated that Pso effectively reduced the levels of the histological damage in rats with TP intervention. The findings from both in vivo and in vitro studies indicate that Pso may mitigate apoptosis, mitochondrial dysfunction, and the inhibition of the Nrf2 signaling pathway induced by TP. Moreover, the effects of Nrf2 signaling inhibitor ML385 on Pso were found to significantly attenuate the above outcomes. Collectively, Pso alleviated TP-induced ovarian damage by inhibiting GC apoptosis driven by mitochondrial dysfunction, and the mechanism was in part associated with the activating Nrf2 signaling pathway. Our research results illuminate the advantageous impact of Pso on TP-induced ovarian injury, providing new insights for the therapeutic comprehension of TP-induced ovarian toxicity.

Note:
Funding declaration: This work was supported by the research project of Hunan University of Chinese Medicine (2024XJZB005).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: All animal procedures were performed in line with the principles of the Animal Experimental Center of Hunan University of Chinese Medicine (reference number: LL2022110913).

Keywords: Psoralen Triptolide Granulosa cell Mitochondrial dysfunction Apoptosis Nrf2