Coreopsis tinctoria Nutt. attenuates ultraviolet A photodamage by suppressing endoplasmic reticulum stress-induced apoptosis via Nrf2 crosstalk

Abstract

Background: Solar ultraviolet A (UVA) induces skin photodamage primarily by triggering endoplasmic reticulum (ER) stress, leading to misfolded protein accumulation and apoptosis. Coreopsis tinctoria Nutt. [Asteraceae] (CT), a medicinal chrysanthemum with antioxidant properties, has potential protective effects against UVA-induced skin injury. This study investigates the molecular mechanisms underlying CT’s photoprotective effects, emphasizing ER stress modulation and activation of antioxidant pathways. Methods: We characterized CT metabolites using UPLC-ESI-MS/MS, identifying 1,288 metabolites with flavonoids as predominant. The anti-UVA effects of CT in human keratinocytes (HaCaT) were assessed via bulk mRNA sequencing, Western blot analysis, immunofluorescence, flow cytometry, and siRNA-mediated knockdown of Nrf2. In vivo, UVA-irradiated murine models received topical CT treatment, with skin damage evaluated through immunohistochemistry and histopathology. Results: CT contains numerous flavonoids that contribute to its antioxidative capacity. In UVA-exposed HaCaT cells, CT significantly reduced apoptosis, inflammatory cytokine release, and reactive oxygen species (ROS) production. It downregulated ER stress markers (CHOP, pIRE1, ATF6), preserved ER morphology, and decreased downstream apoptotic signaling. Nrf2 knockdown experiments revealed that CT’s protective effects depend on Nrf2-mediated antioxidant responses. In vivo, topical CT application attenuated ER stress and skin injury induced by UVA exposure. Conclusion: CT alleviates UVA-induced skin photodamage by concurrently inhibiting all three branches of ER stress and activating Nrf2-driven antioxidant defenses, thereby modulating apoptosis. These findings position CT as a promising natural agent for dermocosmetic and therapeutic strategies against UVA-mediated skin injury.