Unraveling Small Molecule-Mediated Sirtuin 3 Activation at a Distinct Binding Site for Cardioprotective Therapies

  • ACS Cent Sci. 2025 Apr 14;11(5):704-718. doi: 10.1021/acscentsci.5c00023.
Dan Zhang  1 ,  Jifa Zhang  1 ,  Chengyong Wu  1 ,  Yao Xiao  1 ,  Liwei Ji  2 ,  Jiarui Hu  1 ,  Jianjun Ding  3 ,  Tao Li  2 ,  Yiwen Zhang  1 ,  Liang Ouyang  1  4
Affiliations
  • 1. Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 2. Department of Anesthesiology, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 3. School of Food Science and Technology, Jiangnan University, Wuxi 214122, Jiangsu, China.
  • 4. Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, Sichuan, China.
PMID: 40454347 DOI: 10.1021/acscentsci.5c00023
Abstract

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.

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