The glycoprotein GPNMB protects against oxidative stress through enhanced PI3K/AKT signaling in epidermal keratinocytes.

Vitiligo, an autoimmune disease caused by environmental and genetic factors, is characterized by the specific loss of epidermal melanocytes (MCs). IFN-γ, predominantly derived from MC-targeting CD8(+) T cells, plays a key role in vitiligo pathogenesis. Previously, we found that glycoprotein nonmetastatic melanoma protein B (GPNMB) is specifically lost in the basal epidermal layer of vitiligo lesions and downregulated by IFN-γ in normal human epidermal keratinocytes (KCs) (NHEKs). This study aimed to determine the role of KC GPNMB in normal and vitiligo epidermis and demonstrated that GPNMB plays a protective role against H(2)O(2)-induced oxidative stress due to its extracellular domain. In contrast, the NRF2/KEEP1 system was not involved in the anti-oxidative response in NHEKs but was active in MCs. GPNMB knockdown reduced the phosphorylation levels of AKT(T308) and AKT(S473) after H(2)O(2) treatment, accompanied by reduced Dickkopf-1 (DKK1) mRNA and protein production and decreased FOXM1 mRNA expression. These results suggested that GPNMB protects KCs from H(2)O(2)-induced cell death through enhanced PI3K/AKT signaling, and WNT/β-catenin/FOXM1 and DKK1/CKAP4/AKT pathways. Furthermore, a significant increase in thioredoxin-interacting protein (TXNIP) following GPNMB knockdown was observed, indicating the enhanced phosphorylation of JNK and p38 and suppression of WNT/β-catenin signaling. These results suggest that the decreased expression of epidermal GPNMB in vitiligo lesions triggers increased sensitivity to H(2)O(2)-induced oxidative stress and decreased WNT/β-catenin signaling, consistent with the pathological features of the vitiligo epidermis. These findings may enhance our understanding of vitiligo pathogenesis, provide insights into the reduced risk of epidermal cancers, and highlight novel targets for treatment.