Sakuranin attenuates UVB-induced skin damage by preserving mitochondria-ER coupling and restoring redox-organelle homeostasis.

Ultraviolet B (UVB) irradiation elicits complex intracellular stress responses that drive keratinocyte injury and skin photoaging through coordinated disruption of redox homeostasis, mitochondrial dynamics, and endoplasmic reticulum (ER) stress signaling at mitochondria-ER contact sites. This study investigated whether sakuranin (SKR), a naturally occurring flavanone glycoside, exerts photoprotective effects by modulating mitochondria-ER networks under UVB exposure. SKR displayed no cytotoxicity at concentrations up to 100 μM, when administered as a pre-treatment, significantly reduced UVB-induced apoptotic cell death by suppressing cytosolic and mitochondrial reactive oxygen species accumulation, preserving mitochondrial membrane potential, and restoring the balance between DRP1-driven fission and OPA1-mediated fusion. In parallel, SKR markedly attenuated ER stress responses, as evidenced by reduced eIF2α phosphorylation and downregulation of GRP78 and CHOP expression, while live-cell imaging confirmed the preservation of mitochondria-ER contact integrity disrupted by UVB exposure. These protective effects were consistently reproduced in UVB-exposed zebrafish larvae, in which SKR significantly alleviated oxidative stress and ER stress responses. Collectively, these findings demonstrate that SKR provides robust photoprotection by coordinately regulating oxidative stress, mitochondrial dynamics, ER stress signaling, and mitochondria-ER communication, thereby mitigating UVB-induced apoptotic injury and supporting its potential as a natural therapeutic candidate for preventing photoaging and UVB-associated skin disorders.