Abstract

Vitiligo is an acquired depigmentation disorder caused by the destruction or loss of melanocytes. Due to the difficulty in restoring pigmentation, the therapeutic efficacy of current treatments remains limited. Restoring melanocyte function and promoting efficient melanosome transport are critical for successful repigmentation, highlighting the urgent need to elucidate novel mechanisms and identify new therapeutic targets. In this study, SCARB1 (encoding the SR-BI protein) was identified as a hub gene significantly downregulated in lesional skin and melanocytes of vitiligo patients through transcriptomic and bioinformatic analyses. Functional experiments revealed that SCARB1/Scarb1 knockdown reduced melanin content, suppressed the expression of melanogenic markers (MITF, TYR, DCT, TYRP1), and impaired the expression of melanosome transport-related proteins (Rab27a, MLPH, MYO5A). Mechanistically, SR-BI promoted melanogenesis by associating with protein kinase A (PKA) and enhancing PKA/CREB (cAMP response element-binding protein) signaling, as evidenced by decreased levels of phosphorylated CREB and PKA following SR-BI silencing. Importantly, impaired melanogenesis and protein expression caused by Scarb1 knockdown were partially rescued by PKA overexpression. Additionally, zebrafish models demonstrated significantly reduced pigmentation following scarb1 knockout in vivo . These findings uncover a novel role for SR-BI in regulating melanocyte function and melanosome transport, offering a potential therapeutic target for vitiligo treatment.