The Protective Role of Stem Cell Factor (SCF) in Regulating UV-mediated DNA damage in Amelanotic Keratinocytes

Abstract

Vitiligo, a condition characterized by loss of melanocyte and depigmentation, paradoxically associates with a lower risk of skin malignancies. This study explores the protective molecular pathways in vitiligo keratinocytes against UV-induced DNA damage. We uncover a new stem cell factor (SCF)-mediated pathway that induces lipoprotein lipase (LPL) and sirtuin 1 (SIRT1) to counteract UVB-induced cellular damage. SCF treatment decreased γ-H2AX positivity and cyclobutene pyrimidine dimer (CPD) formation strongly, enhanced the health of the mitochondria (elongated morphology, reduced reactive oxygen species and lipid peroxidation), and normalized lipid metabolism through increased LPL expression. Disruption of LPL using siRNA knockdown caused elevated DNA damage and lipid droplet formation, all effects reversed with NO-1886, a selective LPL agonist. In addition, pharmacological or genetic SIRT1 inhibition eliminates SCF-mediated protective effects, positioning SIRT1 as the critical downstream effector in the SCF-LPL- SIRT1 pathway. Vitiligo patient skin biopsy analysis supports SCF and LPL upregulation in lesional epidermis. Collectively, these discoveries identify a new SCF-LPL-SIRT1 pathway, showing that SCF-induced lipid metabolism remodeling is responsible for keratinocyte protection against UV damage and for the natural tumor suppressive milieu in vitiligo skin. These findings disclose possible therapeutic opportunities for preventing UV damage and skin cancer.