TAX1BP1 protects against doxorubicin-induced cardiotoxicity via maintaining mitochondrial function in a mTORC2-SGK1-VDAC1 manner.

OBJECTIVE: The efficacy of doxorubicin (DOX) in treating various cancers is hindered by its associated cardiotoxicity, limiting its clinical utility. Mitophagy dysfunction and impaired mitochondrial function may be significantly involved in the development of DOX-induced cardiotoxicity (DIC). Tax1 (T-cell leukemia virus type I)-binding protein 1 (TAX1BP1) is an autophagic receptor; however, its role in DIC remains elusive. Therefore, the objective of this study was to assess the influence of TAX1BP1 overexpression on DIC and its molecular mechanisms, focusing specifically on mPTP opening and mitophagy in cardiomyocytes. METHODS: Male C57BL/6J mice were intravenously administered recombinant adeno-associated virus serotype-9 (AAV9) carrying Flag-TAX1BP1 and cardiac troponin T (cTNT) promoter (AAV9-cTNT-TAX1BP1). Mice were randomly subjected to a DOX challenge with weekly administration of 4 mg/kg body weight for 5 weeks. RESULTS: TAX1BP1 levels were notably decreased in the cardiac tissues of DIC mice. Cardiac TAX1BP1 overexpression alleviated cardiac remodeling and dysfunction in mice with DIC, with little effect from TAX1BP1 overexpression alone. TAX1BP1 overexpression improved mitochondrial dysfunction and promoted mitophagy in DIC cardiomyocytes. Furthermore, TAX1BP1 interacted with mTOR through its SKICH domain and facilitated the assembly of the mTORC2 complex, thereby initiating SGK1 phosphorylation, limiting the aggregation of VDAC1 and preventing the opening of the mitochondrial permeability transition pore (mPTP) in the cardiomyocytes facing DOX challenge. CONCLUSION: Collectively, our study highlights the significant role of TAX1BP1 in preventing mPTP opening and enhancing mitophagy, which contributes to the mitigation of mitochondrial and cardiac abnormalities associated with DIC. Our findings highlighted the potential therapeutic benefits of targeting TAX1BP1 in patients with DIC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-026-01427-2.