Epigenetic regulation of ACSL4 via H2A monoubiquitylation connects lipid metabolism to BAP1-mediated ferroptosis

The tumor suppressor BRCA1-associated protein 1 (BAP1) encodes a nuclear deubiquitinase that specifically removes H2A monoubiquitination at Lys119 (H2Aub) and plays a crucial role in the epigenetic regulation of gene expression through cooperating with several transcriptional factors and chromatin-modifying enzymes. Our previous studies have confirmed that BAP1 represses SLC7A11-mediated cystine metabolism and promotes ferroptosis-dependent tumor suppression. However, how BAP1 regulates gene expression at the genome level and whether additional mechanisms are involved in the BAP1 regulation of ferroptosis remain unclear. Here, we integrate multi-omics analyses to explore the effects of BAP1-mediated H2Aub deubiquitination on the regulation of chromatin accessibility and gene transcription. Notably, we identified a novel target gene, ACSL4, which is positively regulated by BAP1 and contributes to BAP1-mediated ferroptosis. Importantly, genetic knockout or pharmacological inhibition of ACSL4 prevents the upregulation of lipid biosynthesis and ferroptotic cell death caused by BAP1. In addition, we demonstrated that BAP1-mediated regulation of gene expression and ferroptosis is dependent on ASXL family members instead of other BAP1-associated factors like FOXK1/2, HCFC1, and OGT. Together, our findings uncover a previously unappreciated epigenetic mechanism underlying the regulation of ACSL4 by H2A monoubiquitination, which connects ACSL4-mediated lipid metabolism to ferroptosis driven by BAP1, providing new insights into the understanding of metabolic regulation of BAP1-related diseases such as cancers.