Abstract

Oxidative stress is identified as a potential factor in vitiligo pathogenesis. We aimed here to evaluate whether USP11 regulates the oxidative stress of melanocytes in vitiligo. Human melanocyte PIG1 cells were induced with 1 mM H 2 O 2 and pre-infected with lentiviruses for genetic intervention. The dorsal skin of C57BL/6J mice was applied with 5% H 2 O 2 , and genetic intervention was elicited through adenoviruses. USP11, SIRT3, and TRIM28 were reduced in melanocytes (Melan-A positive) from vitiligo mouse skin tissues and in the H 2 O 2 -induced PIG1 cells. TRIM28 transcriptionally activated USP11 to promote deubiquitination of SIRT3. H 2 O 2 decreased viability and melanin and tyrosinase contents and increased apoptosis and oxidative stress in PIG1 cells. H 2 O 2 induced severe depigmentation of the dorsal skin in mice, reduced melanin deposition in hair follicles, loss of melanocytes, and increased oxidative stress. Overexpression of either USP11 or TRIM28 inhibited H 2 O 2 -induced melanocyte damage and vitiligo, while combined knockdown of SIRT3 or USP11 reversed the effects of USP11 or TRIM28 overexpression. These findings suggest that TRIM28 exerts its effect by reducing oxidative stress in melanocytes through USP11-mediated SIRT3 deubiquitination. This observation provides a mechanistic insight that could inform future therapeutic exploration in vitiligo. Graphical abstract text. The diagram. TRIM28 inhibits oxidative stress damage in melanocytes and alleviates vitiligo by transcriptionally upregulating USP11 and promoting deubiquitination modification of SIRT3.