UVRAG, short for UV radiation resistance associated, is a key regulator of mammalian macroautophagy/autophagy. It interacts with BECN1, PIK3C3, and RUBCN, playing a significant role in autophagy-related pathways and thus is of great biological importance. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions [1,3].

In a mouse model with an inducible cancer-derived frameshift (FS) mutation in UVRAG, the dominant-negative inhibition of wild-type UVRAG impairs stimulus-induced autophagy. This systemic autophagy compromise, especially mitophagy, increases inflammation and associated pathologies. Also, time-dependent autophagy suppression and subsequent CTNNB1/β-catenin activation may be a tumor-promoting mechanism underlying age-related cancer susceptibility [3].

In Alzheimer's disease, UVRAG downregulation during TNF-α-promoted necroptosis impairs autophagy flux, leading to p62 accumulation and subsequent activation of the RIPK1/RIPK3/MLKL cascade and neuronal necroptosis. Overexpression of UVRAG inhibits neuronal necroptosis in cell and mouse models of AD [2].

In colorectal cancer, a frameshift mutation of UVRAG switches its role from a tumor suppressor to an oncogene, promoting tumorigenesis, epithelial-to-mesenchymal transition, and metastasis, while also sensitizing tumors to adjuvant chemotherapy [4].

In conclusion, UVRAG is crucial in autophagy processes. Through model-based research, its roles in inflammation, cancer, and neurodegenerative diseases like Alzheimer's have been revealed. Mouse models with UVRAG mutations have provided insights into the mechanisms of these diseases, suggesting that UVRAG could be a potential target for therapeutic intervention in these disease areas.