Senp6, also known as Sentrin/SUMO-specific protease 6, is a SUMO protease that plays a crucial role in maintaining genomic stability, regulating signaling pathways, and influencing various cellular processes [1-10]. It functions by deconjugating SUMO2/3 polymers from substrate proteins, thus regulating their SUMOylation status. SUMOylation is a post-translational modification that affects protein localization, turnover, and function, and Senp6-mediated deSUMOylation is involved in pathways such as DNA damage response, IFN-I-induced signaling, and microglial polarization [1-10].

In OCP-specific Senp6 knockout mice, smaller skeletons are observed, along with elevated apoptosis and cell senescence in OCPs and chondrocytes, revealing its role in maintaining osteochondroprogenitor homeostasis by suppressing the p53 pathway [2]. In diffuse large B-cell lymphoma, genetic alterations of Senp6 lead to unrestricted SUMOylation, impaired DNA repair, and genomic instability, suggesting it as a tumor suppressor [4]. In cerebral ischemia-reperfusion injury models, Senp6-mediated deSUMOylation of Annexin-A1 promotes microglial polarization and neuroinflammation, while its inhibition reduces brain infarct size and neurological deficits [1,3].

In conclusion, Senp6 is essential for maintaining cellular homeostasis through its deSUMOylation function. Model-based research, especially using KO/CKO mouse models, has revealed its significance in diseases like lymphoma, ischemic stroke, and in processes related to skeletal development. Understanding Senp6's role provides insights into disease mechanisms and potential therapeutic targets for these conditions.