Epigenetic downregulation of MAPKAPK2 exacerbates oxidative stress-induced damage in vitiligo melanocyte cell line...

Vitiligo is an acquired depigmentation disorder caused by melanocyte dysfunction or loss. Oxidative stress is widely considered a key driver to its pathogenesis. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) is implicated in oxidative stress responses, although its role in vitiligo remains uncertain. This study intended to investigate whether epigenetic downregulation of MAPKAPK2 aggravates oxidative stress-induced damage in vitiligo melanocytes.

Human melanocyte lines (PIG1 and PIG3V) were used to model normal and vitiligo conditions. The effects of oxidative stress, DNA demethylation (5-aza-DC), and MAPKAPK2 overexpression were assessed using qRT-PCR, Western blot, ELISA, comet assay, TUNEL, and CCK-8. Pharmacological inhibition of MK2 was employed to evaluate the functional requirement of MAPKAPK2 kinase activity, and key antioxidant pathways, including Nrf2 signaling, were investigated.

MAPKAPK2 expression was notably downregulated in PIG3V cells compared with PIG1 cells (P < 0.05), and further reduced upon H₂O₂ exposure (P < 0.01), suggesting stress-related suppression. Exposure to 5-aza-DC partially restored MAPKAPK2 expression (P < 0.01), implicating DNA methylation in its silencing. Functional assays showed that MAPKAPK2 overexpression significantly alleviated H₂O₂-induced reductions in cell viability, increases in apoptosis, impaired melanogenesis, and oxidative damage (all P < 0.01), while activating the Nrf2/HO-1 antioxidant pathway through suppression of KEAP1 expression and enhancement of Nrf2 nuclear translocation. Genetic knockdown, rescue, and pharmacological inhibition experiments further demonstrated that these cytoprotective effects under oxidative stress were dependent on MAPKAPK2 kinase activity.

Epigenetic silencing of MAPKAPK2 aggravates oxidative damage in vitiligo melanocytes, potentially by attenuating Nrf2-associated antioxidant responses. These findings identify MAPKAPK2 as a functionally relevant and targetable factor in the oxidative pathology of vitiligo.