Effect of inducible overexpression of NRASWT or NRASQ61R in human epidermal melanocytes

Lesional cells reside in a state of oncogene-induced senescence. Here, we show that melanocytes undergoing NRAS-induced senescence exhibit profound alterations in lipid metabolism, together with elevated ferrous iron and lipid peroxidation.

We further show that aldehyde dehydrogenase (ALDH) enzymes protect senescent melanocytes from ferroptosis by limiting lipid peroxidation and damage by lipid-derived aldehydes. Inhibition of ALDH1A1, ALDH1A3 and ALDH1B1 selectively eliminated senescent melanocytes by triggering ferroptotic lipid peroxidation and downstream aldehyde-mediated damage, an effect amplified by SLC7A11 inhibition. In a murine CMN model and in ex vivo cultured human CMN tissue, ALDH inhibition selectively depleted nevus cells.