Targeting Programmed Cell Death in Male Infertility: Pathogenic Mechanisms and Therapeutic Strategies

Narrative review maps five regulated cell death pathways — apoptosis, autophagy, pyroptosis, ferroptosis, efferocytosis — as drivers of spermatogenic failure

Journal: Molecular Biology Reports | Published: 2026-06-16 | Type: Journal Article, Review | PMID: 42301490 Authors: Zhou Runtang, Lv Wenbo, Wang Jinyuan, Xiong Yingguan, Huang Hua, Lei XiaoCan (Clinical Anatomy and Reproductive Medicine Application Institute, Department of Histology and Embryology, China) Funding/COI: Funded by Natural Science Foundation of Guangxi, Yunnan Universities Science & Technology Projects, Hunan Provincial Department of Education. No competing interests declared.

Summary

This is a narrative review synthesizing current knowledge on how five forms of programmed cell death (PCD) — apoptosis, autophagy, pyroptosis, ferroptosis, and efferocytosis — contribute to male infertility. The authors argue that aberrant activation of these pathways in germ cells, Sertoli cells, and Leydig cells disrupts spermatogenesis, often triggered by oxidative stress, inflammation, or metabolic imbalance. Unlike prior reviews that treated these pathways in isolation, this paper attempts to map shared molecular nodes and crosstalk between them.

Data integrity note: The full-text sections provided to this pipeline (Methods, Results, Discussion, Conclusion) are from a separate GBD 2019 epidemiological burden study on male infertility, not from this review article. The abstract is authentic; the full text sections appear to be a data pipeline artifact. Analysis below is based on the abstract.

Claims

• Programmed cell death — not necrosis — is an actively regulated, gene-controlled process essential for testicular homeostasis
• Five PCD pathways are implicated in male infertility: apoptosis, autophagy, pyroptosis, ferroptosis, and efferocytosis
• Dysregulation affects all three key testicular cell populations: germ cells, Sertoli cells, and Leydig cells
• Oxidative stress, inflammation, and metabolic imbalance are the upstream triggers driving aberrant PCD activation
• Efferocytosis — the clearance of dying cells — is included as a distinct mechanism, not merely a consequence of other pathways
• Pathway crosstalk and shared molecular nodes are identified as potential therapeutic targets

Study Quality

This is a narrative review with no disclosed systematic search protocol, no database search terms, no PRISMA flow diagram, and no pre-registered review methodology. That means the authors selected papers at their own discretion — the literature base is unverifiable, and publication bias is uncontrolled. Narrative reviews are useful for conceptual synthesis but cannot weight the relative contributions of each pathway or establish clinical relevance.

The institution is a reproductive medicine research group in China with appropriate domain expertise. The three funding sources are government education and science programs with no pharmaceutical or commercial ties, which is a point in the paper's favor. However, the absence of COI doesn't fix the methodological limitations inherent to a non-systematic review.

Red Flags

• No systematic methodology: no search strategy, no inclusion/exclusion criteria, no quality assessment of included studies — selections are editorially curated, not systematically derived
• Pipeline data mismatch: full-text sections delivered to this feed appear to be from a GBD 2019 burden study, not from this review — raises questions about data integrity upstream
• No clinical data: entirely mechanistic and preclinical; translational relevance to human infertility is asserted, not demonstrated
• Efferocytosis inclusion is non-standard: framing efferocytosis as a PCD pathway alongside apoptosis and ferroptosis is conceptually contested — it is primarily a clearance mechanism
• "Therapeutic targets" framing overreaches: a narrative review identifying molecular nodes cannot validate those nodes as actionable targets without experimental evidence, which this paper does not provide

Strengths

• Covers five PCD mechanisms in a single synthesis, which is broader than most prior reviews in this space
• Explicitly attempts to map pathway crosstalk rather than treating each in isolation
• No pharmaceutical funding or competing interests
• Government-funded academic research with no commercial pressure on conclusions

Verdict

This paper is a map, not a measurement. It consolidates mechanistic literature on five cell death pathways in the context of male infertility — useful as a reading guide for researchers entering the space, less useful as evidence for anything. The narrative format means you're trusting the authors' literature selection, not a reproducible search. The crosstalk angle is the most interesting contribution, but without a systematic search or experimental validation, "potential therapeutic targets" is speculative framing. Read it for orientation; don't cite it as evidence that any specific pathway drives infertility in humans.