Hydroxysafflower yellow a protects against UVA- and UVB-induced skin aging by suppressing cell apoptosis and SASP via targeting JNK and p38 MAPK pathway

Safflower (Carthamus tinctorius L.) is a traditional Chinese medicinal herb that has long been used to promote blood circulation. Its major active component, hydroxysafflor yellow A (HSYA), exhibits potent antioxidant and anti-photoaging properties. However, the mechanisms underlying HSYA's protective effects against skin photoaging remain largely unclear. This study aimed to elucidate how HSYA mitigates skin aging induced by UVA- and UVB-triggered apoptosis and the senescence-associated secretory phenotype (SASP) in keratinocytes and fibroblasts. Damage models were established by exposing BALB/c nude mice, HaCaT keratinocytes, and HSF fibroblasts to either combined or individual UVA and UVB irradiation. Network pharmacology analysis was subsequently performed to explore the molecular mechanisms underlying the anti-photoaging effects of HSYA. The predicted targets and signaling pathways were validated through both in vitro and in vivo experiments. HSYA reduced apoptosis in UVB-damaged keratinocytes and UVA-damaged fibroblasts by regulating the expression of Bcl-2 and Bax and reducing cleavage of PARP and caspase 3. It also suppressed ROS accumulation in both cell types. Furthermore, HSYA inhibited SASP by downregulating the expression of TNF-α, IL-6, IL-8, and matrix metalloproteinases (MMPs). It significantly enhanced type I procollagen expression of skin fibroblasts and promoted collagen fiber deposition in mouse skin, suggesting a reversal of UV-induced senescence of skin fibroblasts. Mechanistically, HSYA exerted its protective effects by inhibiting the activation of the p38 and JNK pathways. Notably, the inhibitory effects of HSYA on p38 and JNK phosphorylation were comparable to those of specific MAPK inhibitors. These findings identify that HSYA exerts the protective effects against UV-induced skin damage through coordinated regulation of oxidative stress, inflammation, apoptosis, and collagen remodeling, in part by targeting the JNK/p38 MAPK pathway. Thus, HSYA emerges as a promising active ingredient for the development of anti-photoaging and skin-rejuvenation products in the future.