Stem cell factor-mediated upregulation of SIRT1 protects melanin-deprived keratinocytes against UV-induced DNA damage in individuals with vitiligo.

Despite the loss of melanocytes, individuals with vitiligo have a significantly lower risk of developing skin malignancies compared to ethnicity-matched controls. The study investigated the molecular mechanisms that protect skin cells (keratinocytes) from UV-B-induced DNA damage in individuals with vitiligo. The study found that upregulation of stem cell factor (SCF) signaling significantly reduced γ-H2AX positivity and cyclobutane pyrimidine dimer formation and improved mitochondrial health (elongated mitochondria, reduced reactive oxygen species [ROS] and lipid peroxidation) in keratinocytes upon UV-B exposure. Interestingly, SCF treatment also reduced lipid droplet accumulation and triacylglyceride levels by upregulating lipoprotein lipase (LPL). Further, siLPL increased DNA damage and lipid droplet (LD) accumulation, while NO-1886, an LPL agonist, reversed both, suggesting a direct link between lipid metabolism and DNA damage. Downregulation of NAD-dependent deacetylase sirtuin1 (SIRT1) with siRNA or with Ex-527, a pharmacological inhibitor of SIRT1, diminished the protective effects mediated by SCF and NO-1886, suggesting SIRT1 to be the final effector protein in the SCF-LPL-SIRT1 signaling axis. Analysis of clinical samples of vitiligo corroborated the upregulation of SCF and LPL in lesional epidermis. In conclusion, our study demonstrates a novel SCF-LPL-SIRT1 signaling axis that confers protection to vitiligo keratinocytes from the harmful effects of UV-B radiation.