Extracellular vesicle-encapsulated GDF15 alleviates doxorubicin-induced cardiotoxicity via the SUB1/TERT/TPP signalling axis

Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but its clinical application is limited by cardiotoxicity. Mitochondrial dysfunction and apoptosis are key mechanisms underlying DOX-induced cardiomyopathy (DIC), while the role of telomerase reverse transcriptase (TERT) and its specific regulatory mechanisms remain unclear. An in vitro DOX-induced H9C2 cardiomyocyte injury model was established. TERT was overexpressed via adenoviral transfection or inhibited using BIBR1532. An in vivo mouse model of DOX-induced acute myocardial injury was constructed, with TERT expression regulated via intramyocardial adenoviral injection. Cardiac function was evaluated by echocardiography, and myocardial pathology was observed via staining. Additionally, exosome-encapsulated growth differentiation factor 15 (EXO-GDF15) was extracted and identified. Its regulatory mechanism on TERT was explored using DNA pull-down and luciferase reporter gene assays. Metabolomics was used to analyze the effect of TERT on mitochondrial metabolites in cardiomyocytes. TERT overexpression reduced DOX-induced apoptosis, increased mitochondrial membrane potential, and promoted autophagy in cardiomyocyte. In mice, TERT overexpression improved cardiac function and alleviated myocardial fibrosis, inflammation, and cardiomyocyte hypertrophy. Conversely, TERT inhibition exacerbated these injuries. EXO-GDF15 could be endocytosed by cardiomyocytes and alleviated DOX-induced myocardial injury by downregulating SUB1 to promote TERT transcription. Luciferase reporter assays showed that SUB1 binds to the BS4 site of the TERT promoter. Metabolomics showed that TERT increased the mitochondrial metabolite thiamine pyrophosphate (TPP) in cardiomyocytes, which alleviated myocardial injury by participating in the tricarboxylic acid cycle. EXO-GDF15 alleviates doxorubicin-induced cardiotoxicity via the SUB1/TERT/TPP signaling axis, thereby providing advanced insights for future DIC treatment. TERT overexpression reduces DOX-induced cardiomyocyte apoptosis, preserves mitochondrial function, and enhances autophagy, while TERT inhibition worsens in vivo cardiac injury. Critically, exosome-encapsulated GDF15 (EXO-GDF15) alleviates DIC by promoting TERT transcription.