Neuropeptide Y drives vitiligo progression via NPYR-mediated NF-κB activation: a novel therapeutic target.

Neuropeptide Y (NPY) is a neurotransmitter involved in stress response and immune modulation and its dysregulation may contribute to the pathogenesis of vitiligo by influencing melanocyte function and autoimmune responses. This study aimed to explore the role and molecular mechanism of NPY in the progression of vitiligo. In vitro, human immortalized keratinocyte (HaCaT) cells were treated with H2O2 to simulate oxidative stress conditions observed in vitiligo. Through specific knockdown of the NPY receptor (NPY2R or NPY4R) achieved by siRNA transfection, combined with techniques such as Western blot (WB), ELISA and RT-qPCR, we found that NPY primarily activated the NF-κB signaling pathway via the NPY2R, thereby inducing the expression of key inflammatory cytokines, including CXCL9, CXCL10, and IL-15. Concurrently, NPY reduced intracellular ROS levels and partially inhibited H2O2-induced keratinocyte apoptosis. In vivo, a H2O2-induced vitiligo mouse model revealed that NPY exacerbated skin depigmentation, promoted NF-κB activation, increased expression of IL-15, and enhanced CD8 + T cell infiltration. In contrast, NPY2R inhibitors effectively reversed these phenotypes. Further assays indicated that NPY treatment decreased MDA content in skin tissue while elevating the activities of SOD and GSH-Px. Moreover, TUNEL staining and WB analysis of cleaved caspase-3 demonstrated that NPY could inhibit melanocyte apoptosis. Overall, this study was the first to demonstrate that NPY promoted the expression of CXCL9, CXCL10, and IL-15 by activating the NPY2R-mediated NF-κB signaling pathway in keratinocytes, thereby synergizing with oxidative stress to recruit CD8 + T cells and drive vitiligo progression.