A medicinal chemistry perspective on SIRT3 modulators in disease treatment

As the primary mitochondrial deacetylase, SIRT3 plays a central role in key biological processes such as cellular energy metabolism, oxidative stress response, and apoptosis regulation. It is also closely associated with the development and progression of neurodegenerative diseases, cardiovascular disorders, and various cancers. With advancing research on its biological functions, SIRT3 has emerged as a promising therapeutic target, leading to the discovery of multiple types of SIRT3 modulators. From a medicinal chemistry perspective, this review systematically summarizes the progress, challenges, and opportunities in the development of SIRT3-targeting drugs. We comprehensively analyze the structure-activity relationships, mechanisms of action, and in vitro/in vivo activities of SIRT3 modulators. Furthermore, this review discusses future research directions, including the design of highly selective modulators, organelle-specific delivery systems, and protease-mediated SIRT3 degradation, offering theoretical and experimental foundations for therapeutic strategies targeting SIRT3-related diseases.