SIRT5 Attenuates Doxorubicin-Induced Acute Cardiac Injury by Modulating PHB2 Succinylation and the Mitophagic Response

Doxorubicin (DOX)–induced cardiac injury remains a major limitation of chemotherapy and is closely linked to mitochondrial dysfunction, oxidative stress, and dysregulated mitophagy. Sirtuin 5 (SIRT5), a mitochondrial deacylation-related protein, has been implicated in mitochondrial homeostasis; however, its role in DOX-induced acute cardiaotoxicity is not fully understood. Here, we investigated whether SIRT5 mitigates acute DOX-induced cardiac injury by regulating prohibitin 2 (PHB2) succinylation and mitochondrial quality control. An acute DOX-induced cardiac-damaged mouse model was established (15 mg/kg for one single dose, i.p.) in male C57BL/6 mice, serum lactate dehydrogenase (LDH), cardiac troponin T (cTnT), and cardiac creatine kinase isoenzyme MB (CK-MB) were elevated, accompanied by reduced cardiac SIRT5 expression. In primary cardiomyocytes, DOX (4 µM, 24 h) downregulated SIRT5 and induced excessive ROS production and apoptosis together with altered mitophagy-related signaling. SIRT5 overexpression attenuated DOX-triggered ROS accumulation and apoptosis and reversed these mitophagy-associated alterations. Mechanistically, PHB2 succinylation was increased upon DOX exposure, whereas SIRT5 overexpression reduced PHB2 succinylation detected by PHB2 immunoprecipitation followed by pan–succinyl-lysine immunoblotting. In addition, SIRT5 showed colocalization and interaction with PHB2. Collectively, our findings suggest that SIRT5 attenuates acute DOX-induced cardiotoxicity, potentially through modulating PHB2 succinylation and the mitophagic response, highlighting the SIRT5–PHB2 axis as a candidate target for alleviating early-onset of DOX-induced cardiac injury. Graphical abstract The proposed protective mechanism by SIRT5 on DOX-induced cardiotoxicity.