Emerging roles of SIRT7 in metabolic homeostasis and related disorders

Metabolic diseases, including type 2 diabetes mellitus, obesity, and metabolic dysfunction-associated steatotic liver disease, are major global health challenges, sharing features such as disrupted glucose-lipid homeostasis, mitochondrial dysfunction, and chronic low-grade inflammation. Among mammalian sirtuins, SIRT7, though poorly characterized, is important for chromatin state, metabolic flux, mitochondrial function, and inflammatory responses in metabolically active tissues. Clinical and preclinical studies link dysregulated SIRT7 to multiple metabolic diseases, with tissue-specific effects on hepatic lipogenesis, insulin signaling, adipose function, and even metabolism-related hepatocellular carcinoma. Despite advances in the development of SIRT7-targeted inhibitors, significant challenges remain, including the absence of selective activators, limited structural characterization, incomplete understanding of tissue-specific regulatory mechanisms, and potential dose-dependent effects. This review integrates current knowledge on SIRT7-mediated regulatory networks and discusses emerging efforts to develop selective SIRT7 modulators, including structural-guided approaches based on AlphaFold models.