SIRT4, a member of the sirtuin family, is an NAD+-dependent enzyme [3,4,6,8]. Sirtuins are known as longevity proteins, and SIRT4 has been reported to have important physiological functions such as promoting DNA damage repair, participating in three-substance energy metabolism, inhibiting inflammatory reactions and apoptosis, and regulating mitochondrial function [1]. It is also involved in pathways like the urea cycle and is associated with many biological processes related to aging, metabolism, and disease [1,2,4,6]. Genetic models, such as KO/CKO mouse models, can be valuable for studying SIRT4's functions.

In Sirt4 knockout cultured cells, higher levels of ornithine transcarbamylase (OTC) carbamylation at lysine 307 (OTCCP-K307) were observed, leading to activated OTC, elevated urea cycle intermediates, and increased urea production via amino acid catabolism. Sirt4 ablation in male mice decreased blood ammonia levels and ameliorated CCl4-induced hepatic encephalopathy phenotypes, revealing its role in safeguarding against cellular ammonia toxicity during amino acid catabolism [2].

In mouse models of osteoarthritis (OA), Sirt4 down-regulation in chondrocytes promoted cellular senescence and cartilage degradation, accompanied by mitochondrial dysfunction, while overexpression of Sirt4 protected against these effects. Gene therapy with a lentiviral vector encoding mouse Sirt4 preserved articular cartilage integrity in OA mouse models [5].

In intestinal fibrosis models, SIRT4 expression was decreased in a TGF-β-dependent manner. SIRT4 impeded extracellular matrix (ECM) deposition by inhibiting glutaminolysis through facilitating the degradation of glutaminase 1 (GLS1), providing a potential therapeutic target for intestinal fibrosis [7].

In pancreatic cancer cells, knockdown of UHRF1, which has a negative correlation with SIRT4, decreased hypoxia-inducible factor (HIF)1α levels and HIF1α-targeted glycolytic genes, suggesting SIRT4 negatively regulates aerobic glycolysis, cell proliferation, and tumor growth in pancreatic cancer [9].

In conclusion, SIRT4 plays crucial roles in multiple biological processes. Model-based research, especially KO/CKO mouse models, has revealed its functions in areas such as ammonia detoxification, chondrocyte senescence and OA, intestinal fibrosis, and pancreatic cancer metabolism. These findings contribute to understanding the mechanisms of related diseases and may offer potential therapeutic targets.