Hydroxytyrosol Improves UV ‐Induced Skin Photoaging via PI3K ‐ AKT / MAPK / JAK ‐ STAT and NF ‐ κB Pathways: Insights From Keratinocytes and In Vivo Validation

ABSTRACT This study investigated the efficacy of hydroxytyrosol (HT), an active ingredient renowned for its antioxidant and anti‐inflammatory properties derived from olive leaves and oil, in mitigating skin photoaging and elucidating its underlying mechanisms. Utilizing a comprehensive methodology that included network pharmacology, molecular docking, molecular dynamics (MD) simulations, quantitative mass spectrometry‐based proteomics, in vitro assays on keratinocytes, and in vivo experiments with a nude mouse model, we assessed the effects of HT against ultraviolet (UV) radiation‐induced skin damage. Our results demonstrated that HT significantly reduces oxidative stress and inflammatory responses, inhibited matrix metalloproteinases (MMPs) activity, mitigates collagen and elastin degradation, enhanced moisture retention, and suppresses apoptosis in keratinocytes. Mechanistically, HT engaged critical signaling pathways such as phosphatidylinositol 3‐kinase (PI3K)‐protein kinase B (AKT), nuclear factor‐kappa B (NF‐κB), mitogen‐activated protein kinase (MAPK), and Janus kinase (JAK)‐signal transducer and activator of transcription (STAT), resulting in improved skin hydration, elasticity, collagen density, attenuation of the senescence‐associated secretory phenotype (SASPs), and restoration of skin integrity in vivo. These findings provide a molecular basis for the anti‐photoaging properties of HT, supporting its potential application as a novel phytotherapeutic agent for the management of UV‐induced skin damage.