Abstract

Ferroptosis, an iron-dependent form of regulated cell death, is crucial for skin homeostasis and pathology. The H3K36-specific dimethyltransferase NSD2 is a key epigenetic regulator involved in a spectrum of physiological processes and contributes to the pathogenesis of various human cancers. However, the epigenetic mechanism governing ferroptosis sensitivity in keratinocytes remains poorly understood. This study revealed the role of NSD2 in regulating ferroptosis in HaCaT keratinocytes. We demonstrated that NSD2 deletion significantly attenuated Erastin-induced redox imbalance and reduced the sensitivity of HaCaT cells to Erastin-induced ferroptosis. RNA-seq analysis revealed that NSD2 deficiency downregulated key ferroptosis-promoting genes, including NCOA4, LPCAT3, and ATG5. Mechanistically, NSD2-mediated H3K36me2 activates their transcription to facilitate ferroptosis in keratinocytes. In addition, functional rescue experiments showed that restoring NCOA4, LPCAT3 or ATG5 expression reversed the ferroptosis resistance caused by NSD2 deficiency. This study identifies NSD2 as a novel critical epigenetic regulator of ferroptosis. It unveils that NSD2 is essential for ferroptosis by synchronously enhancing iron accumulation and lipid peroxidation substrate supply. This provides a new mechanistic link between epigenetic regulation and ferroptosis-related cell fate determination in the skin.