Molecular mechanisms underlying cyclophosphamide-induced ovarian injury and protective strategies

Ehab E Sharata, Taha Bakry, Habiba I. Atta, Hussein Jassim Mohammed, Nazema Shaker Diab, Rofaida Ashraf Atef, Roaa Sayed Hosney, Mahmoud Mohamed Omar, Ramadan A.M. Hemeida
In: Naunyn-Schmiedeberg's Archives of Pharmacology · 2025 · vol. 399(2) , pp. 1951–1985 · doi:10.1007/s00210-025-04550-9 · PMID:40938363 · W4414149086
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Abstract

Cyclophosphamide (CP) is an anti-cancer medication that also treats chronic inflammatory illnesses caused by the immune system. Although CP is widely used, it can occasionally have limited therapeutic efficacy due to its significant combined toxicities. Ovarian damage caused by CP is a major problem for patients, and premature ovarian failure (POF) is a serious side effect of CP that commonly affects female patients. Mechanistic investigations have implicated oxidative stress, inflammatory responses, and apoptosis as critical components in the etiology of CP-induced POF, although the exact process by which this ovarian toxicity occurs remains unclear. After CP causes ovarian cells to generate proinflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB) is activated. The activation of the NLRP3 inflammasome is the subsequent stage. In addition, Nrf2/HO-1 has been identified as an important signaling pathway that mitigates oxidative stress in CP-induced POF due to its anti-inflammatory and antioxidative characteristics. Moreover, several recent studies highlighted the role of α-klotho deficiency in ovarian aging. Quercetin, resveratrol, berberine, curcumin, irbesartan, mirtazapine, sildenafil, atorvastatin, donepezil, cilostazol, moxibustion, LCZ696, buspirone, levomilnacipran, melatonin, diosmin, and azilsartan are some of the agents that may protect against ovarian injury caused by CP, as shown in Graphical abstract. Our goal in writing this study is to provide a concise overview of the possible redox molecular pathways that cause ovarian harm in CP and how to potentially ameliorate them. Finally, investigation into these molecular pathways may pave the way for early ovarian damage relief and for the development of different agent strategies to alleviate CP-mediated POF.

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