A Novel FGF2‐Targeted Inhibitor (N‐trans‐feruloyloctopamine) Suppresses UVB‐Induced Skin Damage and Hyperpigmentation

ABSTRACT Ultraviolet B (UVB) radiation significantly damages skin and causes hyperpigmentation, but effective molecular interventions are limited. This study explores fibroblast growth factor 2's (FGF2) role in UVB‐induced skin damage and identifies N‐trans‐feruloyloctopamine (NFO) as a novel FGF2 inhibitor. NFO effectively reduces UVB‐related skin damage and hyperpigmentation. In UVB‐exposed mice, increased FGF2 expression leads to epidermal thickening, collagen hyperplasia, and immune cell recruitment. FGF2 −/− mice show reduced skin damage and hyperpigmentation. Molecular docking, surface plasmon resonance, and cellular thermal shift assays reveal that NFO binds to and inhibits FGF2, reducing skin inflammation and pigmentation. NFO blocks FGF2 from binding to the FGFR receptor, thereby inhibiting the Ras/Raf/MEK/ERK signaling pathway. This leads to a significant reduction in genes related to immune cell recruitment (CXCL3, CCL4, CCL5) and melanogenesis (MC1R, TYRP1, TYR, DCT). This study clarifies how NFO, as an FGF2 inhibitor, mitigates UVB‐induced skin damage and hyperpigmentation by regulating this pathway, offering insights for developing new treatments for UV‐related skin damage.