Epigenetic regulation of DOT1L methyltransferase activity remodels lipid metabolism to alleviate ferroptosis-induced liver injury

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Abstract

Epigenetic modifications contribute to lipid-related disorders by modulating the expression of key genes involved in lipid metabolism. 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. DOT1L loss remodeled the phospholipid landscape by decreasing PUFA-containing phospholipids while increasing monounsaturated and lysophospholipid species. Mechanistically, DOT1L depletion reduced H3K79me1 and H3K79me2 occupancy at the PLA2G7, ALDH3B1, and PLCXD3 loci, particularly across gene-body regions, while increasing promoter-proximal accessibility and expression of these phospholipid-remodeling genes. These genes suppress ferroptosis by reducing the levels of phospholipids containing polyunsaturated fatty acids (PL-PUFAs). Furthermore, we demonstrated that AMPK phosphorylates DOT1L at Ser786, weakens its association with AF9, and suppresses H3K79 methyltransferase activity and ferroptosis sensitivity. Collectively, our findings reveal the AMPK–DOT1L–H3K79 methylation axis as a novel lipid metabolic pathway that regulates ferroptosis and maintains hepatic homeostasis, offering new therapeutic insights for ferroptosis-related liver injury.

Authors

Jia-ming Hu, Shuo Liu, Zheng-ze Pan, Yi-jia Gao, Wei-wei Cui, Xiao Zhuang, Rong Wang, Ya-jing Han, Jia-xing Liu, Xiang-chuang Fan, Dan-dan Song, Zi-yang Zhang, Wan-yang Sun, Zong-li Zhang, Rong-rong He, Yun-fei Xu, Wei Gu, Chang Pan, Bo Chu