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

Dong-Zhen Cai,

Junda Li, Peng Zhang

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3496 - 3496

Published: April 8, 2025

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 inactivation of GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis-characterized mitochondrial dysfunction disulfide stress due copper overload-exacerbates germ apoptosis via FDX1 activation NADPH depletion. Pyroptosis, mediated NLRP3 inflammasome gasdermin D, amplifies testicular inflammation loss IL-1β/IL-18 release, particularly in response insults. Autophagy maintains homeostasis clearing damaged organelles proteins; however, its dysregulation impairs sperm maturation compromises blood-testis barrier integrity. These pathways intersect shared regulators; reactive oxygen species mTOR modulate autophagy-pyroptosis balance, while Nrf2 bridge ferroptosis-cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise preclinical models. However, challenges persist, tissue-specific roles isoforms, off-target effects pharmacological inhibitors, transgenerational epigenetic impacts toxins. This review synthesizes current molecular insights into implicated male infertility, emphasizing their interplay translational potential for restoring spermatogenic function.

Language: Английский

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

Dong-Zhen Cai,

Junda Li, Peng Zhang

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(8), P. 3496 - 3496

Published: April 8, 2025

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 inactivation of GPX4/Nrf2/SLC7A11 axis, disrupts spermatogenesis under conditions oxidative stress, environmental toxin exposure, or metabolic disorders. Similarly, cuproptosis-characterized mitochondrial dysfunction disulfide stress due copper overload-exacerbates germ apoptosis via FDX1 activation NADPH depletion. Pyroptosis, mediated NLRP3 inflammasome gasdermin D, amplifies testicular inflammation loss IL-1β/IL-18 release, particularly in response insults. Autophagy maintains homeostasis clearing damaged organelles proteins; however, its dysregulation impairs sperm maturation compromises blood-testis barrier integrity. These pathways intersect shared regulators; reactive oxygen species mTOR modulate autophagy-pyroptosis balance, while Nrf2 bridge ferroptosis-cuproptosis crosstalk. Therapeutic interventions targeting these mechanisms have shown promise preclinical models. However, challenges persist, tissue-specific roles isoforms, off-target effects pharmacological inhibitors, transgenerational epigenetic impacts toxins. This review synthesizes current molecular insights into implicated male infertility, emphasizing their interplay translational potential for restoring spermatogenic function.

Language: Английский

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