Senp6, also known as Sentrin/SUMO-specific protease 6, is a SUMO protease that plays a crucial role in maintaining genomic stability, regulating protein SUMOylation, and is involved in multiple cellular pathways [1,3,4,5,6]. SUMOylation is a post-translational modification that affects protein localization, turnover, or function, and Senp6 modulates this process by deconjugating SUMO2/3 polymers from various substrate proteins. It is essential for the normal functioning of cells and is associated with pathways such as DNA damage response, IFN-I-induced signaling, and microglial polarization, among others [1,2,4].

In Senp6-deficient models, various phenotypes have been observed. In OCP-specific Senp6 knockout mice, there are smaller skeletons, elevated apoptosis, and cell senescence in OCPs and chondrocytes, revealing the role of Senp6 in maintaining osteochondroprogenitor homeostasis by suppressing the p53 pathway [5]. In microglia, knockdown of Senp6 using AAV-based techniques in vivo lessened brain ischemic infarct size, decreased neurological deficit scores, and improved motor and cognitive function, indicating its role in microglial polarization and neuroinflammation after cerebral ischemia-reperfusion injury [4]. In diffuse large B-cell lymphoma, loss of Senp6 leads to unrestricted SUMOylation, impaired DNA repair, and genomic instability, suggesting its role as a tumor suppressor [7].

In conclusion, Senp6 is a key regulator in multiple biological processes, mainly through its function in de-SUMOylating proteins. Model-based research, especially KO/CKO mouse models, has revealed its significance in diseases such as ischemic stroke, lymphoma, and skeletal development-related disorders. Understanding Senp6's function provides insights into disease mechanisms and potential therapeutic targets.