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, 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.