Protective efficacy of Met-Ser-Arg against irradiation-related testicular injury†

Ionizing radiation poses a significant risk to male fertility by inducing testicular damage, yet effective protective strategies remain limited. The tripeptide Met-Ser-Arg (MSA) has demonstrated potential in alleviating radiation-induced oxidative stress and lipid metabolic disorders, prompting investigation into its protective effects on the male reproductive system. Male BALB/c mice were exposed to X-ray irradiation (0.5 Gy/day for 5 days) to establish a testicular injury model, followed by MSA treatment. Testicular structure and function were evaluated through histology, electron microscopy, computer-assisted sperm analysis, and quantitative PCR. MSA significantly alleviated radiation-induced testicular damage, restoring the structural integrity and function of spermatogenesis tubules while increasing both the height of the spermatogenic epithelium and germ cell number. Sperm quality and motility were markedly improved, and the expression of several sperm cell molecular markers was favorably adjusted. Mechanistic investigations revealed that MSA regulated lipid metabolism by upregulating fatty acid β-oxidation enzymes, including acyl-CoA synthetase long-chain family member 3 (ACSL3)and carnitine palmitoyl transferase 1A (CPT1A), while downregulating the lipid synthase diacylglycerol O-acyltransferase 2 (DGAT2), thereby reducing lipid droplet accumulation. MSA also attenuated radiation-induced reactive oxygen species and malondialdehyde levels, enhanced antioxidant capacity through upregulation of nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase 1 (HO-1), and preserved mitochondrial structure and function via upregulation of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC1A). Furthermore, MSA reduced apoptosis by lowering the levels of Cleaved-caspase 3 and γH2AX. Collectively, these findings demonstrate that MSA ameliorates radiation-induced testicular injury and improves sperm quality through coordinated regulation of lipid metabolism, antioxidant pathway activation, mitochondrial protection, and apoptosis inhibition, providing a theoretical basis for its potential clinical application in the context of radiotherapy.