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, HINT2 deficiency suppressed sterol regulatory element binding protein 2 activity, downregulating transcription factor A mitochondrial, a critical regulator of complex I. Nicotinamide mononucleotide (NMN) supplementation restored lysosomal function in vitro, while cardiac-specific Hint2 overexpression using adeno-associated virus 9 or adenovirus alleviated DIC both in vivo and in vitro. These findings highlight HINT2 as a key cardioprotective factor that mitigates DIC by restoring the NAD+/NADH ratio, lysosomal function, and autophagy. Therapeutic strategies enhancing HINT2 expression or supplementing NMN may reduce cardiac damage and heart failure caused by DOX.