Role of sirtuin 7 (SIRT7) in hepatic physiology and pathophysiology: mechanism, prospective and therapeutic potential

Sirtuin 7 (SIRT7) is member of the oxidized nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin family of proteins that participate in the regulation of a broad spectrum of biological processes and play central roles in cellular homeostasis. Compared with other sirtuins, SIRT7 has been less studied but has emerged as an interesting regulator of chromatin stability, stress adaptation, and immune responses. In particular, emerging evidence indicates that SIRT7 participates in the regulation of endoplasmic reticulum stress (ER) , lipid metabolism, and mitochondrial function in the liver, all of which are crucial in mediating the development and progression of liver steatosis, alcoholic liver injury, hepatic fibrosis, as well as liver cancer. More importantly, genetic restoration of hepatic SIRT7 or interventions that enhance SIRT7-associated pathways have reduced hepatic steatosis and oxidative liver injury in experimental models. Related approaches have also attenuated hepatocyte apoptosis and fibrosis and reduced hepatic ferroptosis in diabetic mice. Pharmacological inhibition of SIRT7 has attenuated myeloid-driven alcoholic liver injury, promoted the clearance of activated hepatic stellate cells (HSCs), and suppressed the growth and treatment resistance of liver cancer. Collectively, these findings identify SIRT7 as a promising preclinical target for mechanistic and therapeutic investigation in liver diseases. However, current evidence is derived predominantly from cellular and animal models, and direct clinical validation remains lacking. Moreover, no selective SIRT7 activator has yet been validated in liver disease. This review summarizes the current understanding of SIRT7 structure, enzymatic properties, molecular targets, and biological functions, with particular emphasis on its roles in hepatic homeostasis and liver disease progression, and discusses the opportunities and current limitations of SIRT7 as a potential preclinical therapeutic target.