Metabolic Reprogramming in Male Infertility: Mechanistic Integration and Translational Perspectives From Mouse Models

Spermatogenesis is a highly energy-dependent and tightly regulated differentiation process in the male reproductive system, characterized by dynamic, stage-specific metabolic adaptations during spermatogonial proliferation, meiosis and sperm maturation. Accumulating evidence suggests that successful spermatogenesis is associated with a coordinated program of metabolic reprogramming, which involves the sequential and context-dependent utilization of distinct bioenergetic pathways rather than dependence on a single energy source. Importantly, metabolic reprogramming represents a physiological and tightly controlled process, whereas metabolic dysfunction arises from its disruption or dysregulation. Studies using mouse models, supported by single-cell omics and metabolic analyses, indicate stage-associated transitions from glycolysis to oxidative phosphorylation (OXPHOS), followed by increased utilization of alternative substrates such as fatty acids and amino acids during germ cell development. These transitions are orchestrated by interconnected networks involving energy-sensing pathways, endocrine regulation and metabolite-driven epigenetic modifications. Disruption of this finely tuned metabolic reprogramming leads to metabolic dysfunction, characterized by oxidative stress, mitochondrial impairment, meiotic defects and chromatin instability, ultimately compromising spermatogenic homeostasis and contributing to idiopathic male infertility. Consistent evidence from experimental and clinical studies further suggests that systemic metabolic disorders, including obesity, diabetes, and dyslipidaemia, as well as exposure to endocrine-disrupting chemicals, may impair metabolic coupling between Sertoli cells and germ cells, thereby exacerbating testicular metabolic imbalance. These disturbances exacerbate mitochondrial dysfunction, one-carbon metabolic imbalance, and blood-testis barrier (BTB) disruption, ultimately leading to reduced sperm quality and fertility. Building on these insights, we propose a metabolism-centred classification framework that stratifies idiopathic male infertility into glycolysis-impaired, OXPHOS-deficient, lipid-overload, and one-carbon metabolism-dysregulated subtypes. We further discuss the translational potential of targeting metabolic pathways through mitochondrial-directed antioxidants, modulation of energy-sensing signalling, and nutritional interventions. Finally, we highlight the need for future studies integrating in vivo metabolic imaging, testicular organoid models and non-invasive seminal metabolomic biomarkers, alongside well-designed clinical trials, to advance metabolism-based precision diagnostics and therapeutics for male infertility.