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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\u2014characterized by mitochondrial dysfunction and disulfide stress due to copper overload\u2014exacerbates 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-1\u03b2\/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\u2013testis barrier integrity. These pathways intersect through shared regulators; reactive oxygen species and mTOR modulate the autophagy\u2013pyroptosis balance, while Nrf2 and FDX1 bridge ferroptosis\u2013cuproptosis 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 the cell death pathways implicated in male infertility, emphasizing their interplay and translational potential for restoring spermatogenic function.<\/jats:p>","DOI":"10.3390\/ijms26083496","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T05:03:07Z","timestamp":1744174987000},"page":"3496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Interplay of Ferroptosis, Cuproptosis, Autophagy and Pyroptosis in Male Infertility: Molecular Crossroads and Therapeutic Opportunities"],"prefix":"10.3390","volume":"26","author":[{"given":"Difan","family":"Cai","sequence":"first","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junda","family":"Li","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zekang","family":"Peng","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2910-0832","authenticated-orcid":false,"given":"Rong","family":"Fu","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyang","family":"Chen","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feihong","family":"Liu","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwang","family":"Li","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjing","family":"Su","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyun","family":"Li","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0634-8150","authenticated-orcid":false,"given":"Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Health Science Center, Hunan Normal University, Changsha 410013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","unstructured":"WHO TEAM (2023). 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