Serinc2-STAT3 protects against doxorubicin-induced cardiotoxicity via promoting mitochondrial bioenergetics

Doxorubicin (DOX) is a highly effective anthracycline chemotherapy drug that is commonly used in clinical practice. Because of the accumulation of its drug concentration, their clinical use is associated with severe cardiotoxicity. Serine incorporator 2 (Serinc2) had been shown to play an important role in maintaining cell structure and function. Here, the main purpose of this study was to explore the effect of Serinc2 on doxorubicin-induced cardiotoxicity and its mechanism.

Global Serinc2 knockout (Serinc2-KO) and cardiac-specific Serinc2 overexpression mice received a single or repeated DOX injection to establish chronic cardiotoxicity. Cardiac function, oxidative damage, cell apoptosis, and mitochondrial profiles were evaluated. Transcriptome and co-immunoprecipitation analysis were used to screen the underlying molecular pathways. Neonatal rat ventricle cardiomyocytes (NRVMs) were cultured to elucidate the role and mechanism of Serinc2 in vitro.

Our data revealed significantly down-regulated Serinc2 expression in DOX-induced mouse hearts and NRVMs. Serinc2-KO aggravated, while cardiac-specific Serinc2 overexpression alleviated DOX-related myocardial injury, oxidative damage, cell apoptosis, and mitochondrial damage. Mechanistically, Serinc2 deficiency resulted in the impairment of mitochondrial bioenergetics and oxidative phosphorylation in DOX cardiotoxicity. Proteomic profiling and interactome analyses revealed that Serinc2 interacted with STAT3 to increase its phosphorylation and nuclear accumulation, a key factor to regulate mitochondrial bioenergetics. Cardiac overexpression of Serinc2 improves mitochondrial bioenergetics in DOX cardiomyopathy both in vivo and in vitro.

Taken together, it can be concluded that Serinc2 can maintain mitochondrial dynamics and increase mitochondrial bioenergy generation by enhancing STAT3 phosphorylation activity, thereby alleviating oxidative stress, apoptotic responses, and improving doxorubicin-induced cardiac dysfunction.