GPR87 Protects UVB-Damaged Skin by Coordinating Antioxidant, DNA Repair, and Anti-Inflammatory Responses via Nrf2 and PI3K/AKT–NF-κB pathways

GPR87 has been implicated in tumorigenesis, malignant progression, and remodeling of the tumor microenvironment in various cancers; however, its function in the skin remains largely unexplored, despite its high expression in skins. Interestingly, we found that UVB exposure downregulates GPR87 expression in human skin tissues, HaCaT keratinocytes, and mouse skin. Importantly, loss of GPR87 was shown to exacerbate UVB-induced skin injury in GPR87-knockout C57BL/6 mice. In keratinocytes, RNA interference–mediated knockdown of GPR87 resulted in increased reactive oxygen species (ROS) levels. Consistently, both in vivo and in vitro data showed that GPR87 deficiency enhances inflammatory responses and cyclobutane pyrimidine dimer (CPD) accumulation, while attenuating apoptosis in skin cells. Moreover, GPR87 promotes CPD clearance by regulating the XPC expression and ubiquitination, a key component of the nucleotide excision repair pathway. Mechanistically, GPR87 exerts its antioxidant effects by promoting Nrf2 nuclear translocation and inducing downstream antioxidant gene expression. Loss of GPR87 also activates the PI3K/AKT pathway and its downstream effector NF-κB. Notably, AKT inhibitor effectively reversed the GPR87 deficiency–induced CPD accumulation and inflammatory responses. Collectively, these findings demonstrate that GPR87 protects UVB-damaged skin by coordinating antioxidant, DNA repair, and anti-inflammatory responses via Nrf2 and PI3K/AKT–NF-κB pathways, identifying GPR87 as a key endogenous factor in maintaining skin homeostasis under environmental stress. Thus, targeting GPR87 may represent a promising strategy to prevent or mitigate UVB-induced photodamage and related skin disorders.