Study Identifies Metabolic Pathway Linking Hyperglycemia to Vitiligo Progression

New research published in the Journal of Clinical Investigation identified a potential mechanistic link between hyperglycemia and vitiligo progression, suggesting elevated glucose levels may worsen disease activity by activating CD8+ T cells through the succinate/SUCNR1 signaling pathway. The findings identify succinate receptor 1 (SUCNR1) as a potential therapeutic target and further highlight the role of immunometabolism in vitiligo pathogenesis.¹

Hyperglycemia Associated With More Active Disease

To investigate the relationship between hyperglycemia and vitiligo, investigators first conducted a hospital-based case-control study involving 321 patients with vitiligo and 642 healthy controls.

Patients with vitiligo demonstrated a significantly higher prevalence of hyperglycemia than healthy controls (11.84% vs 7.01%). After adjustment for age, sex, BMI, smoking status, and alcohol use, hyperglycemia remained independently associated with vitiligo (adjusted OR, 1.781). The association was even stronger among patients with progressive disease, where hyperglycemia occurred in 15.02% of patients compared with 5.56% of those with stable vitiligo (adjusted OR, 3.006). Investigators also observed increasing rates of hyperglycemia with increasing disease severity.¹

These observations were supported in a mouse model, where hyperglycemia resulted in larger depigmented lesions, increased CD8+ T-cell infiltration, and greater melanocyte loss than mice with vitiligo alone.¹

Succinate Emerged as a Key Metabolic Driver

To better understand the underlying biology, investigators performed targeted metabolomic analyses on serum samples from 30 patients with vitiligo and 30 age- and sex-matched healthy controls. Among the metabolites evaluated, succinate emerged as the strongest candidate linking hyperglycemia with disease progression. Serum succinate concentrations were substantially higher in patients with vitiligo than in healthy controls (219.00 μmol/L vs 80.95 μmol/L), were elevated in patients with progressive compared with stable disease, and correlated positively with Vitiligo Area Scoring Index (VASI) scores. Succinate levels were also increased in lesional blister fluid and correlated with both serum glucose concentrations and depigmentation severity in experimental models.¹

Mechanistic Findings Point to SUCNR1

Mechanistic experiments demonstrated that elevated glucose increased succinate production, which subsequently activated CD8+ T cells through succinate receptor 1 (SUCNR1).

Investigators found that SUCNR1 expression was elevated in circulating and lesional CD8+ T cells from patients with vitiligo. Exposure to high glucose or succinate further increased SUCNR1 expression and enhanced markers of CD8+ T-cell activation, including granzyme B and perforin production. Pharmacologic inhibition or genetic deletion of SUCNR1 substantially reduced these immune responses and attenuated depigmentation in mouse models.

The study also demonstrated that succinate promoted keratinocyte production of the chemokines CXCL9 and CXCL10 by stabilizing hypoxia-inducible factor-1α (HIF-1α). These chemokines recruit autoreactive CD8+ T cells into the skin, providing another mechanism through which hyperglycemia may amplify local inflammation.¹

Clinical Implications

Although the study does not establish that improving glycemic control will alter vitiligo outcomes, it provides mechanistic evidence linking metabolic dysfunction with disease activity. The investigators concluded that the study "uncovered the molecular mechanism by which hyperglycemia promoted the progression of vitiligo" through a succinate-mediated immune-metabolic pathway. The findings suggest the succinate/SUCNR1 pathway may represent a novel therapeutic target for limiting CD8+ T-cell activation and slowing disease progression.¹

The findings complement current therapeutic strategies targeting immune pathways such as IL-15 and JAK signaling, suggesting that metabolic pathways may also contribute to disease activity. Together, these data add to growing evidence that immunometabolism may represent another avenue for future therapeutic development in vitiligo.

References:

1. Kang P, Chang Y, Wang T, et al. Hyperglycemia aggravates vitiligo through succinate/SUCNR1-mediated T cell activation. J Clin Invest. 2026;136(12):e200316. doi:10.1172/JCI200316.