Vitiligo, a common autoimmune dermatosis, has a pathogenesis hypothesized to involve oxidative stress-induced immune-mediated melanocyte death. However, the role of oxidative stress in triggering autoimmunity during the early stages of vitiligo, along with its regulatory mechanisms and complex interactions, remains incompletely understood. Keratinocytes, as key initiating cells in vitiligo, secrete various chemokines, primarily C-X-C motif ligand 9 and 10 (CXCL9,10), under oxidative stress to recruit autoreactive immune cells targeting melanocytes. Hypoxia-inducible factor-1α (HIF-1α), a highly conserved transcription factor sensitive to oxidative stress, has been revealed to orchestrate cytokine expression and cellular immune functions. Based on this, the present study investigated the association between oxidative stress and HIF-1α in keratinocytes, and elucidated HIF-1α as a critical molecule bridging oxidative stress and autoimmunity in vitiligo. We initially observed significantly elevated HIF-1α levels in both the serum and depigmented lesions of vitiligo patients. Mechanistically, we demonstrates that HIF-1α serves as a potential biomarker associated with vitiligo progression, and through binding to the respective promoters of CXCL9 and CXCL10, regulates their expression and secretion in keratinocytes at the transcriptional level under oxidative stress, thus motivating peripheral blood mononuclear cells (PBMCs) migration to potential downstream melanocyte damage. HIF-1α activation further amplifies cellular oxidative stress damage in keratinocytes, collectively exacerbating the pathogenesis process of vitiligo. Our fundings suggest that the HIF-1α-CXCL9/10 pathway represents a promising therapeutic target for counteracting abnormal immune activation under oxidative stress in vitiligo.
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