Journal Article Epublish 1 citation
PubMed: 40705191 DOI: 10.1007/s11033-025-10845-0
Molecular hydrogen attenuates cisplatin-induced nephrotoxicity by modulating β-hydroxybutyrate metabolism.
Mol Biol Rep 52(1):751
Authors: Yan Tian, Huilan Su, Yunxi Chen, Xiaomeng Geng, Yafang Zhang, Yu Wang, Wenjie Tang, Weiping Fan, Jianjun Zhou, Youzhen Wei
Affiliations
- State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Road, 200120, Shanghai, P.R. China. Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030001, China.
- State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Road, 200120, Shanghai, P.R. China.
- Department of Neonatology and NICU, The Affiliated Taian City Central Hospital of Qingdao University, Taian, 271000, China.
- State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Road, 200120, Shanghai, P.R. China. Research Institute of Heart Failure, Science Innovation Center, Department of Cardiovascular Surgery, East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
- Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan, 030001, China.
- State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Road, 200120, Shanghai, P.R. China.
- State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, 150 Jimo Road, 200120, Shanghai, P.R. China. Research Center for Translational Medicine, Jinan People's Hospital, Shandong First Medical University, Jinan, 271100, China. Hydrogen Medicine Center, Taian City Central Hospital, Qingdao University, Taian, 271000, China. Department of Rehabilitation Medicine, Jinan Hospital (Jinan City Rehabilitation Hospital), Jinan, Shandong, 250013, P.R. China.
Abstract
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 (H 2) 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 H 2 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 H 2 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
H 2 inhalation significantly attenuated cisplatin-induced kidney injury by reducing inflammation and apoptosis in renal tissue. Transcriptomic analysis revealed that H 2 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 H 2-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 H 2's tissue-protective effects and offer a theoretical foundation for its potential clinical application in mitigating chemotherapy-induced kidney injury.
MeSH
Up-Regulation, Immunohistochemistry, Molecular Biology, Kidney, Drug Therapy, Therapeutics, Apoptosis, Tissues, Chemotherapy