Sleep deprivation impairs follicular development attributable to granulosa cell pyroptosis mediated by S100A8/A9-driven macrophage M1 polarization

Feb 27, 2026Science advances

Sleep loss harms egg follicle growth by causing cell death linked to immune cell changes driven by S100A8/A9

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Abstract

Sleep deprivation disrupted follicular development and compromised early embryonic potential in female mice.

Immunoregulatory mechanisms related to sleep deprivation may contribute to ovarian damage.
Acetaminophen administration could alleviate the negative impacts of sleep deprivation on ovarian function.
RNA sequencing indicated an up-regulation of genes associated with neutrophils, M1 macrophage polarization, and pyroptosis in ovarian tissues.
S100A8/A9 was shown to activate the TLR4/Myd88/NF-κB pathway, which may induce M1 macrophage polarization and granulosa cell pyroptosis.
Findings suggest potential strategies for fertility preservation in individuals experiencing sleep deprivation.

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Sleep disorders and deficiencies can up-regulate pro-inflammatory mediators, but their potential adverse impact on ovarian function remains not fully understood. In this study, we investigated the immunoregulatory mechanisms underlying sleep deprivation (SD)-induced ovarian damage and the effects on follicular development. We found that SD disrupted follicular development and compromised early embryonic developmental potential in female mice. Notably, the use of the anti-inflammatory drug acetaminophen can effectively alleviate the adverse effect. Bulk and single-cell RNA sequencing of ovarian tissues revealed a notable up-regulation of neutrophil-associated genes, including,, the macrophage M1 polarization gene set, and pyroptosis-related genes in granulosa, immune, and mesothelial cells. Further experiments conducted both in vivo and in vitro verified that S100A8/A9 activates the TLR4/Myd88/NF-κB pathway, which induces the polarization of M1 macrophages and leads to pyroptosis of granulosa cells. Collectively, this study provides molecular insight into strategies for fertility preservation in individuals experiencing sleep deprivation, including those with occupational circadian rhythm disruptions. S100a8S100a9

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Sleep deprivation impairs follicular development attributable to granulosa cell pyroptosis mediated by S100A8/A9-driven macrophage M1 polarization

Abstract

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