P2ry6, the pyrimidinergic receptor, is a G-protein-coupled receptor. It is involved in multiple biological processes through activating Gq/phospholipase C-β signaling pathway [2]. It has been implicated in various pathways and diseases, highlighting its biological importance. Genetic models, especially knockout mouse models, have been crucial for studying its function.

In mouse models, P2ry6-deficient mice showed resistance to 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin papilloma formation, indicating its role as a positive regulator of skin tumorigenesis through modulating Hippo/YAP and Wnt/β-catenin signaling pathways [3]. Surprisingly, in UVB-induced skin carcinogenesis, P2ry6-deficient mice exhibited promoted skin papilloma formation, suggesting it may act as a tumor suppressor by regulating the PI3K/AKT signaling pathway [4]. Also, global deletion of P2ry6 from mice did not compromise viability, while in tumors, its deletion inflamed the tumor microenvironment to inhibit tumor growth, as it enhances prostaglandin E2 production to drive immunosuppression [2]. In macrophages, P2ry6 may be an endogenous receptor of C16:0 ceramide-induced inflammasome activation, and its inhibition alleviates ceramide-induced atherosclerosis aggravation [1].

In conclusion, P2ry6 plays diverse and context-dependent roles in biological processes and diseases. Gene knockout mouse models have been instrumental in revealing its functions in skin carcinogenesis, tumor-associated immunosuppression, and atherosclerosis. Understanding P2ry6 can provide potential therapeutic targets for related diseases.

References:

1. Zhang, Siting, Lin, Hui, Wang, Jiale, Sun, Jinpeng, Kong, Wei. 2025. Sensing ceramides by CYSLTR2 and P2RY6 to aggravate atherosclerosis. In Nature, 641, 476-485. doi:10.1038/s41586-025-08792-8. https://pubmed.ncbi.nlm.nih.gov/40049228/

2. Xu, Xilong, Lu, Yi, Cao, Longzhi, Cui, Yue, Han, Ting. 2024. Tumor-intrinsic P2RY6 drives immunosuppression by enhancing PGE2 production. In Cell reports, 43, 114469. doi:10.1016/j.celrep.2024.114469. https://pubmed.ncbi.nlm.nih.gov/38996067/

3. Xu, Peng, Wang, Caibing, Xiang, Wan, Ye, Xiyun, Dang, Yongyan. 2022. P2RY6 Has a Critical Role in Mouse Skin Carcinogenesis by Regulating the YAP and β-Catenin Signaling Pathways. In The Journal of investigative dermatology, 142, 2334-2342.e8. doi:10.1016/j.jid.2022.02.017. https://pubmed.ncbi.nlm.nih.gov/35304248/

4. Xu, Peng, Liu, Tanglin, Yang, Zile, Ye, Xiyun, Dang, Yongyan. 2024. P2RY6 deletion promotes UVB-induced skin carcinogenesis by activating the PI3K/AKT signal pathway. In Cancer science, 116, 56-66. doi:10.1111/cas.16378. https://pubmed.ncbi.nlm.nih.gov/39435731/