Interplay of Ferroptosis, Cuproptosis, Autophagy and Pyroptosis in Male Infertility: Molecular Crossroads and Therapeutic Opportunities

作者：Difan Cai, Junda Li, Zekang Peng, Rong Fu, Chuyang Chen, Feihong Liu, Y. Li, Yanjing Su, Chunyun Li, Wei Chen · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26083496 · 被引用次数：25 · 研究领域：Birth, Development, and Health、Ferroptosis and cancer prognosis、Pregnancy and preeclampsia studies

Male infertility is intricately linked to dysregulated cell death pathways, including ferroptosis, cuproptosis, pyroptosis, and autophagy. Ferroptosis, driven by iron-dependent lipid peroxidation through the Fenton reaction and inactivation of the GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions of oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis-characterized by mitochondrial dysfunction and disulfide stress due to copper overload-exacerbates germ cell apoptosis via FDX1 activation and NADPH depletion. Pyroptosis, mediated by the NLRP3 inflammasome and gasdermin D, amplifies testicular inflammation and germ cell loss via IL-1β/IL-18 release, particularly in response to environmental insults. Autophagy maintains testicular homeostasis by clearing damaged organelles and proteins; however, its dysregulation impairs sperm maturation and compromises blood-testis barrier integrity. These pathways intersect through shared regulators; reactive oxygen species and mTOR modulate the autophagy-pyroptosis balance, while Nrf2 and FDX1 bridge ferroptosis-cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise in preclinical models. However, challenges persist, including the tissue-specific roles of gasdermin isoforms, off-target effects of pharmacological inhibitors, and transgenerational epigenetic impacts of environmental toxins. This review synthesizes current molecular insights into th...