Fig. 1: BAP1 promotes ferroptosis through different metabolic pathways.

Under homeostatic conditions, cells maintain an effective antioxidant defense system. However, in specific cellular contexts, BAP1 disrupts this balance by repressing SLC7A11 expression through the deubiquitination of H2AK119ub at its promoter, which limits cystine uptake and reduces glutathione (GSH) synthesis. As a consequence, GPX4 activity becomes impaired, weakening the cellular antioxidant defense system. In the presence of polyunsaturated fatty acids (PUFAs), lipid peroxides accumulate within cellular membranes, ultimately triggering membrane rupture and ferroptotic cell death. In addition, BAP1 promotes ferroptosis by upregulating ACSL4 (acyl-CoA synthetase long-chain family member 4). ACSL4 catalyzes the esterification of CoA to specific PUFAs, facilitating their incorporation into membrane phospholipids. These PUFA-containing phospholipids are highly susceptible to peroxidation, thereby increasing cellular sensitivity to ferroptosis. ACSL4 long-chain acyl-coenzyme A (CoA) synthetase 4, ASXL1 Additional Sex combs Like 1, BAP1 BRCA1-Associated Protein 1, GPX4 Glutathione Peroxidase 4, GSR Glutathione Reductase, GSH reduced glutathione, GSSG glutathione disulfide, LOX Lipoxygenase, LPCAT3 Lysophosphatidylcholine Acyltransferase 3, NADP⁺ Nicotinamide Adenine Dinucleotide Phosphate (oxidized form), NADPH Nicotinamide Adenine Dinucleotide Phosphate (reduced form), POR NADPH–cytochrome P450 Oxidoreductase, PL-PUFA-OOH Phospholipid Polyunsaturated Fatty Acid Hydroperoxide, PUFA Polyunsaturated Fatty Acid, PUFA-PL PUFA-containing Phospholipid, SLC7A11 Solute Carrier Family 7 Member 11.