ABSTRACT 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.
Xi et al. (Mon,) studied this question.