Expert Opinion on Therapeutic Targets · Oct 27, 2026

What are the potentials of the different sirtuin proteins as therapeutic targets?

By Fabbrizi E, Hailu GS, Mancini A et al.

INTRODUCTION: Sirtuins (SIRT1-7) are NAD⁺-dependent lysine deacylase and mono-ADP ribosyl transferase enzymes that integrate metabolic status with epigenetic regulation, genome maintenance, mitochondrial homeostasis, and adaptive stress responses. Their dysregulation is implicated in cancer, neurodegeneration, cardiometabolic disorders, inflammation, and aging-associated pathologies, positioning the sirtuin family among the most attractive yet mechanistically complex target classes in contemporary drug discovery. AREAS COVERED: This review critically examines the therapeutic potential of each mammalian sirtuin isoform through the combined perspectives of structural biology, disease validation, chemical tractability, and translational feasibility. Small-molecule activators and inhibitors, allosteric ligands, mechanism-based covalent modulators, and targeted protein degraders are systematically discussed, together with emerging patent activity and recent biological evidence. Literature published up to early 2026 was analyzed through comprehensive searches of PubMed, Scopus, Web of Science, SciFinder, clinical trial registries, and patent databases, with particular emphasis on studies reporting isoform-selective modulation, cellular target engagement, in vivo efficacy, and translational biomarkers. EXPERT OPINION: Sirtuin pharmacology has evolved from proof-of-concept natural products to highly selective chemical probes and event-driven modalities. Among current targets, SIRT2 and SIRT6 show the most favorable balance between biological validation and chemical tractability, whereas mitochondrial sirtuins represent a promising but still underdeveloped frontier for precision therapeutic intervention.

doi.org/10.1080/14728222.2026.2755133PubMed 42937058Interventions