Hyperglycemia aggravates vitiligo through the succinate/SUCNR1 axis

Vitiligo is an autoimmune skin disease characterized by depigmentation, mainly due to CD8+ T cell-mediated destruction of melanocytes. Hyperglycemia exacerbates autoimmune responses and is associated with vitiligo; however, the underlying immunometabolic mechanisms are poorly understood. Here, we confirmed the correlation between hyperglycemia and vitiligo in a case-control study and further demonstrated that hyperglycemia aggravated vitiligo based on a mouse model. Targeted metabolomics identified succinate as the potential metabolite mediating hyperglycemia-aggravated vitiligo. Mechanistically, succinate promotes the activation of CD8+ T cells through SUCNR1 and promotes keratinocytes to secrete CXCL9 and CXCL10 by enhancing the stability and nuclear translocation of HIF-1α, facilitating the skin-homing of CD8+ T cells. Thus, hyperglycemia aggravates vitiligo through succinate/SUCNR1 axis-regulated CD8+ T cell hyperactivation. Our study not only elucidates the long-observed yet mechanistically obscure clinical phenomenon of hyperglycemia accelerating vitiligo progression but also highlights the potential of SUCNR1 as a therapeutic target for hyperglycemia-associated vitiligo.