Epigenetic regulation of DOT1L activity remodels lipid metabolism to alleviate ferroptosis-induced liver injury [ATAC-seq1]

Accumulating evidence suggests that lipid metabolism-mediated ferroptosis drives the progression of metabolic associated steatohepatitis (MASH) and liver injury. However, whether epigenetic mechanisms remodel lipid metabolism to regulate ferroptosis-induced liver damage remains unclear.

Here, through pharmacological screening of epigenetics-related compounds and CRISPR-Cas9-based screening targeting epigenetic factors, we identified DOT1 Like Histone Lysine Methyltransferase (DOT1L) as a key sensitizer of hepatocytes to ferroptosis and subsequent liver injury, whereas inhibition of DOT1L reverses the phenomenon. Mechanistically, DOT1L catalyzes H3K79 methylation via its enzymatic activity, leading to transcriptional repression of phospholipid metabolism genes, including PLA2G7, ALDH3B1, and PLXCD3.