Exosomes from rat bone marrow mesenchymal stem cells improve rat azoospermia by activating the SIRT1/Nrf2/HO-1 signaling axis

Background /Objective Non-obstructive azoospermia (NOA) stands as a primary contributor to male infertility, with effective therapeutic options currently unavailable. Currently, there are no drug-based treatment options available, while assistive technologies rely on accessible sperm, which are often unavailable in cases of severe azoospermia (NOA). Exosomes derived from bone marrow mesenchymal stem cells (BM-MSCs) have gained considerable interest due to their capability to facilitate tissue repair and influence oxidative stress. This research aimed to explore the potential of BM-MSC-derived exosomes in enhancing busulfan-induced NOA in a rat model by activating the SIRT1/Nrf2/HO-1 signaling pathway. Methods Initially, exosomes were extracted from rat BM-MSCs and subsequently characterized. A rat model of busulfan-induced NOA was then developed, followed by the administration of exosomes through intratesticular injection. We assessed the impact on testicular volume, weight, histopathology, oxidative stress markers, and the expression of proteins related to the SIRT1/Nrf2/HO-1 signaling pathway. Results The findings from the experiments indicated that the administration of exosomes led to a substantial improvement in testicular volume and weight, in addition to a reduction in histopathological damage. Moreover, exosomes increased the levels of spermatogonial markers VASA and DAZL and. Indicators of oxidative stress showed that exosomes considerably boosted the activities of CAT, SOD, and GSH, simultaneously decreasing MDA concentrations. Through Western blot analysis, it was verified that exosomes triggered the SIRT1/Nrf2/HO-1 signaling pathway, elevating the expression of SIRT1, Nrf2, HO-1, and NQO-1. Nonetheless, the therapeutic effects of exosomes were countered by treatment with ML385 and EX527, suggesting that their efficacy relies on the activation of the SIRT1/Nrf2/HO-1 signaling axis. Conclusion It can be inferred that exosomes derived from BM-MSCs reduce oxidative stress, improve testicular tissue integrity, and promote spermatogenesis via activation of the SIRT1/Nrf2/HO-1 signaling pathway, thereby effectively addressing NOA. This observation presents a new potential approach for treating NOA.