TSPO integrates redox and immune homeostasis in dermal fibroblasts to restrain vitiligo pathogenesis.

Abstract

Vitiligo is a chronic depigmenting disorder characterized by oxidative stress-driven melanocyte loss and T cell-mediated immune activation. While melanocytes and keratinocytes have been extensively studied, the contribution of dermal fibroblasts to the oxidative and immune microenvironment remains unclear. Here, we identify the mitochondrial translocator protein (TSPO) as a key regulator of redox, inflammatory, and adhesion signaling in dermal fibroblasts. TSPO expression was markedly upregulated in both H2O2-treated fibroblasts and skin biopsies from vitiligo patients, suggesting a compensatory response to oxidative injury. TSPO deficiency aggravated mitochondrial dysfunction, lipid peroxidation, and apoptosis, while its overexpression restored mitochondrial potential, ATP production, and calcium homeostasis. Mechanistically, TSPO activated the p62/Keap1/Nrf2/HO-1 pathway to enhance antioxidant defense and concurrently suppressed NF-κB, NLRP3, and STAT1 signaling, reducing the expression of pro-inflammatory mediators and adhesion regulators. Pharmacological activation of TSPO with the high-affinity ligand Ro5-4864 restored mitochondrial function, reinforced antioxidant capacity, and alleviated depigmentation in an H2O2-induced vitiligo mouse model, while also diminishing CD8+ T cell infiltration and enhancing HO-1 expression. Our findings establish TSPO as a mitochondrial safeguard in dermal fibroblasts, integrating redox control and inflammatory restraint, and highlight TSPO ligands as promising therapeutics for vitiligo.

Key Findings

• TSPO expression is upregulated in dermal fibroblasts under oxidative stress and in vitiligo patient skin biopsies.
• TSPO activates the p62/Keap1/Nrf2/HO-1 pathway to enhance antioxidant defense and suppresses pro-inflammatory signaling pathways (NF-κB, NLRP3, STAT1).
• Pharmacological activation of TSPO with Ro5-4864 restores mitochondrial function, reduces depigmentation, and decreases CD8+ T cell infiltration in a vitiligo mouse model.

Clinical Significance

Citation

Lv Jinpeng, Yin Chuanwei, Yu Wenhaoet al.. TSPO integrates redox and immune homeostasis in dermal fibroblasts to restrain vitiligo pathogenesis. Free radical biology & medicine. 2026-Aug-16.