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

• Published in: The FASEB journal 2024-11, Vol.38 (22), p.e70198-n/a
• Main Authors: Brahmbhatt, Hemang D., Chowdhary, Manish, Gupta, Rohit, Priya, Anshu, Kundu, Akta, Singh, Praveen, Dhamija, Sonam, Gupta, Aayush, Singh, Archana
• Format: Article
• Language: English
• Subjects: Adult; DNA Damage; Female; Humans; Keratinocytes - metabolism; Keratinocytes - radiation effects; Male; Melanins - biosynthesis; Melanins - metabolism; Reactive Oxygen Species - metabolism; Signal Transduction; SIRT1; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; stem cell factor; Stem Cell Factor - genetics; Stem Cell Factor - metabolism; Ultraviolet Rays - adverse effects; Up-Regulation; UV radiation; Vitiligo; Vitiligo - metabolism
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202400550R

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. SCF‐LPL‐SIRT‐1 axis in keratinocytes: Addition of stem cell factor (SCF) upregulates lipoprotein lipase (LPL) in keratinocyte cells, which promotes lipolysis and confers protection to keratinocytes from the harmful effects of UV‐B, including DNA damage, ROS generation, mitochondrial dysfunction by activating SIRT1, the final effector protein in the SCFcKIT/LPL/SIRT1 signaling axis.