Oxidative Stress-Related Programmed Cell Death in Male Infertility: Focussing on Ferroptosis

Review maps three oxidative stress-driven cell death pathways in testicular tissue, spotlighting ferroptosis as an understudied mechanism

Journal: Journal of Cellular and Molecular Medicine | Published: 2026-05 | Type: Narrative Review | PMID: 42178618 Authors: Sanei-Ataabadi N, Aboutalebi F, Dormiani K, Nasr-Esfahani MH (Royan Institute for Biotechnology, Isfahan, Iran) Funding/COI: Neither disclosed

Summary

Oxidative stress kills testicular cells in at least three ways: apoptosis (the classical caspase-mediated route), autophagy (cell self-digestion), and ferroptosis, an iron-dependent pathway only recently linked to male infertility. This review argues that ferroptosis — triggered when the antioxidant enzyme GPX4 fails and lipid peroxidation runs unchecked — deserves more attention than it currently gets in infertility research. No original data are presented; this is a synthesis of existing literature.

Claims

• Elevated reactive oxygen species (ROS) impair spermatogenesis by activating caspases and generating mitochondria-derived free radicals, culminating in DNA damage and apoptotic cell death
• Autophagy functions as an alternative programmed cell death in male germ cells under oxidative stress, and interacts with apoptosis in ways the authors describe as "complex" (no quantification provided)
• Ferroptosis is caspase-independent and initiated by two events: inactivation of glutathione peroxidase 4 (GPX4) and dysfunction of the cystine/glutamate transporter system Xc⁻, both leading to iron-dependent lipid peroxidation
• The review frames apoptosis, autophagy, and ferroptosis as collectively determining the fate of testicular cells under oxidative stress — suggesting therapeutic targets across all three pathways

Study Quality

This is a narrative review, not a systematic review or meta-analysis. The authors did not register a protocol, report a search strategy, define inclusion/exclusion criteria, or assess study quality across the papers they cite. That means cherry-picking is possible and there is no way for readers to verify the evidence base is representative. The absence of any funding or conflict-of-interest disclosure is an additional problem: both Royan Institute affiliations and the journal should require these disclosures, and omitting them removes a basic transparency check.

The science being synthesized is legitimate — GPX4, system Xc⁻, and ferroptosis are well-established in oncology and neuroscience — but the translation to male infertility is early-stage. Most of the underlying ferroptosis research in testicular tissue relies on animal models, not human spermatogenesis data.

Red Flags

• No funding or COI disclosed — neither is explained nor acknowledged
• Narrative rather than systematic review: no search strategy, no PRISMA flow, no quality appraisal of cited studies
• No original data; no effect sizes, sample sizes, or p-values from the review itself
• Ferroptosis-in-infertility literature is largely animal-based; the clinical relevance to human infertility is extrapolated, not demonstrated
• "Focusing on ferroptosis" is stated in the title, but the framework treats all three pathways somewhat equally — the focus is less sharp than advertised

Strengths

• Ferroptosis is a legitimate and underexplored mechanism in reproductive biology; synthesizing it alongside apoptosis and autophagy is conceptually useful
• The GPX4/system Xc⁻ axis is a plausible therapeutic target with existing pharmacological tools (ferrostatin-1, liproxstatin) that could be tested in infertility models
• Royan Institute has a credible reproductive biology research program
• Published in a peer-reviewed journal with reasonable scope for this topic

Verdict

A conceptually useful map of an underexplored territory, undercut by sloppy execution. The case that ferroptosis matters in male infertility is plausible — GPX4 is expressed in spermatids and oxidative stress is real in infertile men — but this review doesn't build the case rigorously. No systematic search, no quality assessment of the underlying studies, no funding disclosure. Read it as an orientation to the pathway rather than evidence that ferroptosis is a clinically significant driver of human male infertility. The next paper worth watching would be a study that actually measures ferroptotic markers in semen or testicular biopsies from infertile men.