Histidine triad nucleotide-binding protein 2 attenuates doxorubicin-induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice.

ABSTRACT: Doxorubicin (DOX) is an effective chemotherapy drug widely used against various cancers but is limited by severe cardiotoxicity. Mitochondria-lysosome interactions are crucial for cellular homeostasis. This study investigates the role of histidine triad nucleotide-binding protein 2 (HINT2) in DOX-induced cardiotoxicity (DIC). We found that HINT2 expression was significantly upregulated in the hearts of DOX-treated mice. Cardiac-specific Hint2 knockout mice exhibited significantly worse cardiac dysfunction, impaired autophagic flux, and lysosomal dysfunction after DOX treatment. Mechanistically, HINT2 deficiency reduced oxidative phosphorylation complex I activity and disrupted the nicotinamide adenine dinucleotide NAD⁺/NADH ratio, impairing lysosomal function. Further, HI

SUBMITTER: Jiang H 

PROVIDER: S-EPMC11831189 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature