Heat stress-mediated oxidative damage in male germ cells: potential protective effects of L-citrulline

Male factors contribute to approximately half of all infertility cases globally, with heat stress recognized as a major environmental determinant of impaired male reproductive function. Extensive research indicates that heat stress disrupts spermatogenesis through multiple pathways, including testicular oxidative stress (OS), compromise of the blood-testis barrier, and dysregulation of the spermatogonial stem cell niche. As global temperatures rise, the prevalence of heat-induced reproductive impairment is increasing, underscoring the urgent need to identify safe and effective interventions that target the underlying oxidative damage. L-citrulline demonstrates significant potential in the field of male reproductive protection. However, existing reviews primarily focus on general discussions of antioxidants, lacking a systematic analysis of the specific mechanisms of L-citrulline. This review systematically synthesizes current knowledge on the molecular mechanisms of heat stress-induced oxidative injury in male gametes. Particular emphasis is placed on the multifaceted protective role of L-citrulline, which acts through synergistic mechanisms involving modulation of the arginine-nitric oxide (NO) pathway, preservation of mitochondrial homeostasis, restoration of autophagy flux, and suppression of apoptotic signaling. By integrating experimental and clinical evidence, this analysis aims to elucidate both the translational potential and the key scientific challenges of L-citrulline supplementation in male reproductive health. The review seeks to advance the translation of L-citrulline from basic research to clinical practice and to propose novel nutritional strategies for improving fertility outcomes in men exposed to heat stress.