B7-H3 promotes skin photodamage through ITGA2-NRF2-TFAM-mediated mitochondrial oxidative stress.

Ultraviolet radiation (UVR) exposure drives skin photodamage, which constitutes the fundamental basis of both photoaging and photocarcinogenesis, by disrupting mitochondrial homeostasis and inducing reactive oxygen species (ROS) accumulation. Although B7-H3 (CD276) is recognized as an immune-checkpoint molecule involved in tumor metabolism, its role in UVR-induced cutaneous photodamage and the associated redox imbalance remains undefined. Here we show that B7-H3 is elevated in acute and chronic photodamaged human skin as well as in UVR-induced mouse (female) and cell models. Genetic deletion or antibody blockade of B7-H3 attenuates ROS accumulation, preserves mitochondrial function, and reduces photodamage. Mechanistically, B7-H3 interacts with integrin α2 (ITGA2) to impair antioxidant signaling by inhibiting the nuclear translocation of nuclear factor erythroid 2-related factor 2 (NRF2) and disrupting the nuclear respiratory factor 1 (NRF1)-transcription factor A, mitochondrial (TFAM) pathway, ultimately disrupting mitochondrial biogenesis and redox balance. Furthermore, treatment with an anti-B7-H3 blocking monoclonal antibody alleviates photodamage and preserves mitochondrial function. Collectively, these findings indicate that the skin-resident B7-H3/ITGA2 interaction contributes to photodamage via disrupting TFAM expression, suggesting that targeting B7-H3 may represent a promising therapeutic strategy for skin photodamage and related disorders.