Background Nephrotoxicity is a common adverse effect of many chemotherapeutic agents and represents a major dose-limiting factor in cancer treatment. Therefore, developing effective renoprotective strategies is urgently needed. Molecular hydrogen (H₂) has emerged as a therapeutic agent with potent antioxidant and anti-inflammatory properties, selectively scavenging hydroxyl radicals and alleviating tissue injury. However, the protective effects and underlying mechanisms of H₂ in chemotherapy-induced acute kidney injury (AKI) remain poorly understood. Methods A cisplatin-induced AKI mouse model was established with or without H₂ administration. Kidney injury biomarkers were evaluated, and levels of inflammation and apoptosis were assessed using TUNEL staining, ELISA, and immunohistochemistry. To investigate the underlying mechanisms, RNA sequencing was performed, followed by heatmap, Venn diagram, and volcano plot analyses to identify differentially expressed genes. KEGG pathway enrichment analysis was used to explore metabolic alterations upon H₂ treatment in cisplatin-induced nephrotoxicity. Subsequently, metabolic alterations were validated through a series of in vivo and in vitro experiments, including ELISA, flow cytometry, qRT-PCR, western blotting, and immunohistochemistry. Results H₂ inhalation significantly attenuated cisplatin-induced kidney injury by reducing inflammation and apoptosis in renal tissue. Transcriptomic analysis revealed that H₂ upregulated the ketone body metabolic pathway, particularly enhancing β-hydroxybutyrate (β-HOB) synthesis via increased expression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). Functional assays confirmed that H₂-mediated upregulation of HMGCS2 and β-HOB contributed to its renoprotective effects. Conclusion Molecular hydrogen confers protection against cisplatin-induced nephrotoxicity by modulating β-HOB metabolism through upregulation of HMGCS2, thereby suppressing renal inflammation and apoptosis. These findings provide new insights into the metabolic mechanism underlying H₂’s tissue-protective effects and offer a theoretical foundation for its potential clinical application in mitigating chemotherapy-induced kidney injury. Graphical Abstract

Despite being the most common form of chronic liver disease, there are still no approved drugs for thetreatment of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to elucidate the therapeutic effects and possible mechanisms of hydrogen (H2) inhalation in mice with NAFLD. Male C57BL/6 mice (6 weeks old) were fed either a 60% fat diet (high-fat diet [HFD]) or a 10% fat diet (normal diet) for 11 weeks. Then, H2 was administered to random HFD-fed mice for another 11 weeks before they were euthanized. Biochemical analysis of serum samples, histological analysis of liver and ileum samples, 16S rRNA sequencing analysis of stool samples, and analysis of the expression levels of related factors by enzyme-linked immunosorbent assay were conducted to determine the effect of H2 intervention on NAFLD. H2 inhalation alleviated hyperglycemia and impaired glucose tolerance; decreased the serum concentrations of triglycerides, cholesterol, alanine aminotransferase, aspartate aminotransferase, lipopolysaccharide, and tumor necrosis factor-alpha; and ameliorated liver injury by a HFD, although no weight loss was observed. Interestingly, H2 inhalation increased the relative abundance of Akkermansia muciniphila and decreased the Firmicutes-to-Bacteroidia ratio in the intestinal tract of NAFLD mice. These data indicate that H2 alleviated the symptoms of NAFLD by increasing the abundance of A. muciniphila in the intestine. Thus, H2 may be a new potential treatment strategy for patients with NAFLD.