Molecular hydrogen attenuates cisplatin-induced nephrotoxicity by modulating β-hydroxybutyrate metabolism.

Abstract

Using a cisplatin-induced acute kidney injury (AKI) mouse model, this study examined the renoprotective effects of H2 gas inhalation and the underlying mechanisms. H2 inhalation markedly reduced renal inflammation and apoptosis, as assessed by TUNEL staining, ELISA, and immunohistochemistry. RNA sequencing followed by KEGG pathway enrichment analysis revealed activation of the ketone body metabolic pathway, characterized by elevated expression of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and consequent enhancement of β-hydroxybutyrate (β-HOB) synthesis. A series of in vivo and in vitro validation experiments, including flow cytometry, qRT-PCR, and western blotting, confirmed that H2-driven upregulation of HMGCS2 and β-HOB was responsible for the observed renoprotective outcomes. These findings identify a metabolic mechanism by which molecular hydrogen mitigates chemotherapy-associated kidney injury.

Mechanism

H2 inhalation upregulates the ketogenic enzyme HMGCS2, enhancing β-hydroxybutyrate (β-HOB) synthesis. Elevated β-HOB levels subsequently suppress inflammatory signaling and apoptosis in renal tissue, thereby conferring protection against cisplatin-induced nephrotoxicity.