SIRT6 mitigates doxorubicin-induced cardiomyopathy via amelioration of mitochondrial dysfunction: A mechanistic study implicating the activation of the Nrf-2/FUNDC1 signaling axis.

Abstract

Doxorubicin-induced myocardial injury, characterized by myocardial hypertrophy and heart failure (HF), represents a primary contributor to end-stage cardiovascular mortality associated with anthracycline drugs. Prior research has elucidated that SIRT6-mediated oxidative processes and mitochondrial metabolic reprogramming are pivotal in sustaining energy metabolism during mitochondrial damage in cardiomyocytes. In the aftermath of doxorubicin-induced myocardial injury, myocardial hypertrophy and fibrosis exacerbate the impairment of cardiac ejection function, resulting in elevated myocardial oxygen consumption. This condition is accompanied by disrupted ATP production, diminished mitochondrial biogenesis, and inadequate synthesis of new mitochondrial DNA, collectively triggering necroptosis and apoptosis pathways. Our preliminary experimental results have confirmed that SIRT6, associated with traditional medicine, exerts cardioprotective effects. Nevertheless, the interaction between SIRT6 and Nrf-2-mediated mitochondrial biogenesis in the context of doxorubicin-induced HF and myocardial hypertrophy remains inadequately understood. The generation of mitochondria is a key mechanism that is involved in DNA repair and cell cycle management.