Sirt6, a member of the Sirtuin family, is a class III histone deacetylase and a key epigenetic regulator. It has diverse biological functions such as deacetylation, defatty-acylation, and mono-ADP-ribosylation, playing a pivotal role in regulating lifespan, DNA repair, gene expression, and telomeric maintenance [3].

Sirt6 deficiency in chondrocytes exacerbates osteoarthritis progression, as seen in mouse models where specific ablation of Sirt6 in chondrocytes led to enhanced surgical destabilization of medial meniscus-induced osteoarthritis and accelerated age-associated OA, along with increased cartilage damage and osteophyte formation [1,5]. In vascular smooth muscle cells of CKD mice, VSMC-specific SIRT6 knockdown led to severe vascular calcification, while SIRT6-transgenic mice showed alleviated VC [2]. In diabetic periodontitis, myeloid-specific deletion of SIRT6 in mice led to unresolved inflammation and aggravated periodontitis [4]. In podocytes, podocyte-specific deletion of Sirt6 in two mouse models (diabetic nephropathy and adriamycin-induced nephropathy) exacerbated podocyte injury and proteinuria [6].

In conclusion, Sirt6 plays essential roles in multiple biological processes. Model-based research, especially through gene knockout mouse models, has revealed its significance in diseases like osteoarthritis, vascular calcification in CKD, diabetic periodontitis, and proteinuric kidney disease. Understanding Sirt6 provides potential therapeutic targets for these diseases.