Targeting AMPK Networks for Male Reproductive Health: Mechanisms and Emerging Therapies

Male infertility is an escalating global health issue, frequently associated with metabolic problems like obesity, diabetes, and age. Recent evidence designates AMP-activated protein kinase (AMPK) as a pivotal regulator linking energy balance to male reproductive function. AMPK regulates essential activities such as spermatogenesis, metabolic support of Sertoli cells, and steroidogenesis in Leydig cells, as well as sperm motility, capacitation, and the acrosome reaction. At the molecular level, AMPK coordinates signaling networks that include mTOR, SIRT1, PGC-1α, and FOXO to modulate mitochondrial function, oxidative stress, and autophagy-related quality control. Dysregulation of AMPK during metabolic and environmental stress results in compromised spermatogenesis, diminished sperm quality, mitochondrial malfunction, and reduced testosterone synthesis. Targeting AMPK signaling constitutes a possible therapeutic approach for enhancing male reproductive health. Pharmacological agents like metformin and AICAR, together with natural bioactive substances, lifestyle modifications, and exercise mimetics, have shown promise in reestablishing metabolic equilibrium and improving reproductive results. Moreover, combinatorial strategies that integrate antioxidants and autophagy modulators may yield synergistic advantages. Nonetheless, obstacles concerning tissue selectivity, optimum dose, and clinical translation persist. Future perspectives highlight precision medicine, biomarker-directed therapies, and the incorporation of metabolic health into fertility treatment. AMPK-targeted treatments collectively provide a novel and mechanistically sound method for addressing male infertility.