Unraveling Small Molecule-Mediated Sirtuin 3 Activation at a Distinct Binding Site for Cardioprotective Therapies
Dan Zhang, Jifa Zhang, Chengyong Wu, Yao Xiao, Liwei Ji, Jiarui Hu, Jianjun Ding, Tao Li, Yiwen Zhang, Liang Ouyang
Abstract
High Resolution Image Download MS PowerPoint Slide Sirtuin 3 (SIRT3), a pivotal mitochondrial deacetylase, plays a critical role in restoring mitochondrial function, particularly through the activation of autophagy. Despite its promise as a cardioprotective target, developing SIRT3 activators and their therapeutic applications remains challenging. Here, we report the identification of SKLB-11A, a SIRT3 activator with submicromolar affinity and high efficacy. Structural and mutagenesis analyses revealed a unique allosteric site for SKLB-11A in SIRT3, where a conformational change in Leu298 drives its potent activation. Subsequent studies demonstrated that SKLB-11A drives autophagy/mitophagy signaling pathways, effectively preventing mitochondrial dysfunction, and improving cardiac dysfunction in both doxorubicin (Dox)-induced cardiotoxicity and myocardial ischemia/reperfusion (I/R) models. Collectively, our data highlight the potential of pharmacological SIRT3 activation as an effective therapeutic strategy for cardioprotection. SKLB-11A, as a first-in-class SIRT3 allosteric activator with a distinct binding mode, not only offers a valuable tool for exploring the physiological and pathological roles of SIRT3 deacetylation but also holds promise for the development of targeted cardioprotective therapies.