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 role in the skin remains largely unexplored, despite its abundant expression in skin. Here, we found that UVB exposure markedly downregulated GPR87 expression in human skin tissues, HaCaT keratinocytes, and mouse skin. Importantly, genetic deletion of Gpr87 exacerbated UVB-induced skin injury in C57BL/6 mice. In keratinocytes, RNA interference–mediated knockdown of GPR87 increased reactive oxygen species (ROS) levels. Both in vivo and in vitro data further showed that GPR87 deficiency aggravated inflammatory responses and cyclobutane pyrimidine dimer (CPD) accumulation while attenuating apoptosis in skin cells. Moreover, GPR87 facilitated CPD clearance by regulating the expression and ubiquitination of XPC, a key component of the nucleotide excision repair pathway. Mechanistically, GPR87 enhances antioxidant defense by promoting Nrf2 nuclear translocation and the expression of downstream antioxidant genes. In parallel, loss of GPR87 activates the PI3K/AKT pathway and its downstream effector NF-κB. Notably, pharmacological inhibition of AKT effectively reversed the GPR87 deficiency–induced CPD accumulation and inflammatory responses. Collectively, these findings demonstrate that GPR87 protects against UVB-induced skin damage by coordinating antioxidant defense, DNA repair, and anti-inflammatory responses through Nrf2 and PI3K/AKT–NF-κB pathways, establishing GPR87 as a key endogenous factor in maintaining skin homeostasis under UVB stress. Thus, targeting GPR87 may provide a promising strategy for preventing or alleviating UVB-induced photodamage and related skin disorders.