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Study · In vitro (cells) · 2025

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

Jiang H, Zhang J, Jia D, Liu L, Gao J, Zhang B, Dong Z, Sun X, Yang W, Ou T, Ding S, He L and 4 more

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Shi Y, Hu K, Sun A, Ge J

MedComm17 Feb 2025Cited by 5 (Europe PMC)

PMID39968501 (opens in a new tab)PMCIDPMC11831189 (opens in a new tab)DOI10.1002/mco2.70075 (opens in a new tab)PepBankPUB-39968501
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Summary

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.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study1

1 result from studies that gave the peptide. No result from this study comes from people.

  1. 01LabIn vitro (cells)Mechanism

    In vitro, NMN supplementation restored lysosomal function in the study of HINT2 and doxorubicin cardiotoxicity.

    In plain wordsIn cells, NMN restored lysosomal function in a study of HINT2 and doxorubicin damage.

    Peptide
    NMN (nicotinamide mononucleotide)
    Outcome
    MixedLysosomal function
    Study

    n: not reported in source

    In vitro HINT2 deficiency model
    Outcome group
    Receptor activity and mechanism · Cardiovascular
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Nicotinamide mononucleotide (NMN) supplementation restored lysosomal function in vitro

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    21 Oct 2026, 15:58 UTC

    Study results updated

  2. Version 1

    21 Oct 2026, 12:50 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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