{"doi":"10.1002/cac2.12231","title":"Phospholipase iPLA2β acts as a guardian against ferroptosis","abstract":"Ferroptosis, a form of iron-dependent regulated cell death caused by excessive accumulation of lipid hydroperoxides, has been associated with various pathological conditions and diseases [1]. Excessive ferroptosis has been causally associated with acute kidney injury, cardiovascular, neurodegenerative and hepatic diseases, whereas impaired ferroptosis in premalignant cells has been shown to contribute to tumor development [2, 3]. To escape from ferroptotic cell death, cells have been equipped with several antioxidant defense systems against lipid peroxidation (Figure 1). Glutathione peroxidase 4 (GPX4) suppresses ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols at the expense of its cofactor glutathione (GSH) [4]. Ferroptosis suppressor protein-1 (FSP1, also known as AIFM2), a NAD(P)H-dependent oxidoreductase located on the plasma membrane, catalyzes the reduction of ubiquinone to ubiquinol, a radical trapping antioxidant that suppresses ferroptosis independent of the GSH-GPX4 axis [5, 6]. In addition, dihydroorotate dehydrogenase (DHODH), an enzyme involved in the de novo pyrimidine biosynthesis pathway, inhibits ferroptosis by reducing ubiquinone to ubiquinol in the inner mitochondrial membrane [7]. Most lipid peroxidation occurs in polyunsaturated fatty acid-containing phospholipids (PUFA-PLs; PUFAs are fatty acids that harbor more than one double bond). Due to the chemical features of double bonds in PUFAs, PUFA-PLs are exquisitely vulnerable to peroxidation in cellular environments rich in iron and oxygen. One major oxidized PUFA-PL species that is believed to trigger ferroptosis is 15-hydroperoxy-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE) [8]. However, how cells neutralize 15-HpETE-PE (and other oxidized PUFA-PLs) and escape from ferroptotic cell death remains incompletely understood. The phospholipase A2 (PLA2) gene family encodes protein enzymes that specifically hydrolyze the sn-2 ester bond on PLs, yielding free fatty acids and lysophosphatidic acids. Calcium-independent phospholipase A2β (iPLA2β), a member of the PLA2 family, is a cytosolic protein that is catalytically active in the absence of calcium and can be stimulated by ATP. In response to stress or injury, iPLA2β preferentially releases free fatty acids (particularly PUFAs, such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid) from the sn-2 position of PLs. While iPLA2β was initially implicated as a housekeeping enzyme in membrane remodeling, recent studies have suggested an engaged role of iPLA2β in a variety of cellular processes, including calcium homeostasis, apoptosis, and inflammation, and its dysregulation has been genetically linked to diverse human diseases, such as Parkinson's disease (PD), male infertility, cardiovascular abnormalities, and cancer [9]. However, the underlying mechanisms by which iPLA2β dysregulation is linked to these human diseases or pathological conditions still remain largely unknown. Two recent studies revealed that iPLA2β preferentially hydrolyzes peroxidized PLs, such as 15-HpETE-PE, and acts as a GPX4-independent repressor of p53-driven ferroptosis [10, 11]. These findings further suggest that iPLA2β is a promising therapeutic target for cancer therapy and that its mutation may be relevant to PD. Sun et al. [10] examined the specific hydrolytic activity of iPLA2β, revealing that both 1-stearoyl (SA)-2-ETE-PE and 1-SA-2-15-HpETE-PE (one specific 15-HpETE-PE) were highly hydrolyzed by iPLA2β. Further studies from both experimental analyses and computational modeling suggested that 1-SA-2-15-HpETE-PE is likely the preferred substrate for iPLA2β. R747W is a loss-of-function mutant in iPLA2β that is associated with infantile neuroaxonal dystrophy and adult-onset dystonia-parkinsonism. Notably, the R747W mutant was shown to exhibit lower hydrolytic activity toward 1-SA-2-15-HpETE-PE than did the wild-type iPLA2β protein. Likewise, the phospholipase activity of iPLA2β towa","journal":"Cancer Communications","year":2021,"id":170392,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9503,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":323854,"name":"Guang Lei","orcid":"0000-0002-3282-0666","position":1,"is_corresponding":false},{"id":334736,"name":"Li Zhuang","orcid":"0000-0001-9056-7681","position":2,"is_corresponding":false},{"id":104623,"name":"Boyi Gan","orcid":"0000-0001-8884-6040","position":3,"is_corresponding":false},{"id":323856,"name":"Chao Mao","orcid":"0000-0002-8685-8539","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-18T23:46:24.040760Z","pmid":"34657380","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}