Melatonin's Sex‐Specific Protection Against High‐Salt Diet and Irradiation‐Induced Multi‐Organ Injury Through Microbiota–Metabolite Interactions

With the evolution of dietary habits and the widespread application of radiation therapy, high-salt diet (HSD) and irradiation (IR) have become significant public health concerns. This study aims to investigate the protective effects of melatonin (MLT) against multi-organ damage induced by HSD combined with whole-abdominal irradiation (WAI), with a focus on its gender-specific mechanisms. Using a C57BL/6 J mouse model of HSD and IR injury, we employed a multi-omics approach to evaluate MLT's therapeutic effects. Results demonstrated that both oral and intraperitoneal administration of MLT significantly mitigated HSD and WAI-induced damage to renal and intestinal tissues while restoring expression of intestinal tight junction proteins and mucin-2 (MUC2), which is the main intestinal mucin forming the mucus barrier. Further investigations revealed that MLT showed sex-dependent associations with the gut microbiota-metabolite axis. Under HSD conditions, it primarily regulates microbial balance via the tryptophan metabolic pathway, whereas post-IR exposure, its regulation shifts toward specific metabolites. Additionally, MLT alleviates cognitive impairment. These findings provide crucial experimental evidence for developing personalized radiation protection strategies.