Ergothioneine rescues obesity-induced testicular dysfunction via dual restoration of steroidogenesis and mitochondrial redox homeostasis

  • Redox Biol. 2026 Apr:91:104090. doi: 10.1016/j.redox.2026.104090.
Xiaomin Li  1 ,  Jiajing Lin  1 ,  Man Wu  1 ,  Feixue Han  1 ,  Shuyan Chen  2 ,  Hongfei Ke  1 ,  Zhiying Huang  1 ,  Tianwen Peng  1 ,  Yu Lan  1 ,  Xin Fu  1 ,  You Che  3 ,  Zhicong Chen  4 ,  Geng An  5
Affiliations
  • 1. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial clinical Research Center for Obstetrics and Gynecology, Guangdong Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
  • 2. The First People's Hospital of Zhaoqing, Zhaoqing, Guangdong, China.
  • 3. HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, HongKong, China.
  • 4. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial clinical Research Center for Obstetrics and Gynecology, Guangdong Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address: [email protected].
  • 5. Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial clinical Research Center for Obstetrics and Gynecology, Guangdong Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China. Electronic address: [email protected].
PMID: 41719756 DOI: 10.1016/j.redox.2026.104090
Abstract

Background: Although obesity is closely linked to reduced male fertility, the specific testicular metabolic and redox mechanisms driving impaired spermatogenesis remain elusive.

Methods: Using a high-fat diet (HFD) mouse model, combined with multi-omics profiling, cellular assays, and ex vivo human testis cultures, we show that chronic HFD feeding progressively disrupts sperm quality, seminiferous architecture, and steroidogenic capacity.

Results: Despite unchanged testis weight, HFD significantly reduced sperm density by 21.6% and motility by 44.9%. Transcriptomic and metabolomic analyses revealed a marked suppression of Oxidative Phosphorylation and depletion of steroidogenic intermediates. Notably, ergothioneine (ET) was identified as the only metabolite consistently 8 reduced across time-course analyses, highlighting its potential as a testis-intrinsic biomarker of cumulative redox stress. ET supplementation (100 mg/kg/day) markedly restored seminiferous epithelial organization and increased the expression of spermatogenic markers. Functionally, ET alleviated the intracellular oxidative burden by reducing lipid peroxidation (TBARS levels decreased by 1.5-fold), and restoring antioxidant enzyme activities. ET enhanced mitochondrial stability, preserving mitochondrial membrane potential (ΔΨm) and reducing mitochondrial superoxide (O2• -) overproduction. Mechanistically, ET reactivated the canonical PKA-CREB-StAR signaling cascade in Leydig cells, reinstating androgen biosynthesis (in vivo DHT increased 1.3-fold, P < 0.01). Finally, ex vivo human testis cultures confirmed that ET attenuated oxidative stress indicators (reducing fluorescence intensity by 2.1-fold) and enhanced testosterone release by 1.4-fold.

Conclusion: These findings establish progressive ET depletion as a hallmark of obesity-induced testicular dysfunction and demonstrate that ET supplementation restores steroidogenesis and mitochondrial redox homeostasis, providing a robust mechanistic basis for antioxidant-guided interventions in male infertility.

Keywords
Ergothioneine; Mitochondrial redox balance; Obesity-induced testicular dysfunction; Oxidative stress; Steroidogenesis.
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