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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