{"doi":"10.1093/lifemeta/loae008","title":"Lipid-derived radical-trapping antioxidants suppress ferroptosis","abstract":"Ferroptosis, characterized by lipid peroxidation-mediated cell demise, is governed by a nuanced interplay of lipid species influencing its vulnerability. Two recent publications in Nature discovered 7-dehydrocholesterol, a cholesterol precursor, as a radical-trapping antioxidant that can suppress ferroptosis, thereby presenting a novel metabolic target to improve ferroptosis-related cancer therapy. Oxidative stress arises from the generation of reactive oxygen species and other free radicals, which cause damage to vital biomolecules, such as lipids, proteins, and DNA. This damage disrupts cellular function and integrity, ultimately precipitating cell death. Among various forms of oxidative cell death, the pharmacological induction of ferroptosis is emerging as an attractive anticancer strategy to suppress tumor growth, particularly in traditionally drug-resistant cancer cells [1]. The molecular mechanism of ferroptosis is heterogeneous and plastic [2]. Classical ferroptosis is initiated by iron-dependent Fenton reactions and subsequent lipid peroxidation [3]. This process results in oxidative damage to membrane lipids, particularly polyunsaturated fatty acid (PUFA)-containing phospholipids, leading to the accumulation of toxic lipid products that induce membrane dysfunction, rupture, and cell demise. Conversely, cells can deploy multiple levels of defense mechanisms to clear or limit oxidative damage and lipid peroxidation products, especially phospholipid hydroperoxides (PLOOHs) (Fig. 1). One such defense mechanism is mediated by the master antioxidant enzyme, glutathione peroxidase 4 (GPX4), which neutralizes lipid peroxides by reducing PLOOH into phospholipid alcohols. Several GPX4-independent enzymes, including apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as ferroptosis suppressor protein 1), dihydroorotate dehydrogenase (DHODH), and GTP cyclohydrolase 1 (GCH1), can produce metabolites with free radical-trapping antioxidant (RTA) activity in a context-dependent manner (Fig. 1). RTAs operate by chemically reacting with free radicals, effectively trapping them, and thus averting further damage. Unlike traditional antioxidants, which primarily function by donating electrons to stabilize free radicals, RTAs physically capture and neutralize radicals by forming stable complexes with them. 7-DHC acts as a radical trapping antioxidant protecting ferroptosis. 7-DHC serves as an intermediate metabolite in the distal cholesterol biosynthesis pathway, synthesized by SC5D and metabolized by DHCR7 for cholesterol synthesis. In the context of ferroptosis, 7-DHC functions as a radical-trapping antioxidant, inhibiting the initiation of lipid peroxidation and consequent cell death. This antioxidant activity complements other GPX4-dependent and GPX4-independent surveillance systems, such as the AIFM2–COQ10 axis, DHODH–COQ10 axis, and GCH1–BH4 axis. PLOOH, phospholipid hydroperoxide; BH4, tetrahydrobiopterin; COQ10, coenzyme Q10. While understanding the lipid metabolism of ferroptosis remains a central topic in this field, the existence of endogenous lipids or metabolites with RTA activity remains uncertain. However, two recent complementary studies conducted by Freitas et al. and Li et al. published in Nature have illuminated this area by suggesting an unexpected role of the cholesterol precursor, 7-dehydrocholesterol (7-DHC), as a natural suppressor of ferroptotic cancer cell death through RTA activity [4, 5] (Fig. 1). By employing a genome-wide CRISPR–Cas9-based screen, both research teams independently pinpointed a crucial enzyme involved in cholesterol synthesis, 7-DHC reductase (DHCR7), as a key gene regulating ferroptosis induced by GPX4 inhibitors, such as RAS-selective lethal 3 (RSL3) and ML210, in Pfa1 or HEK293T cells, respectively. DHCR7 deficiency led to the accumulation of its substrate, 7-DHC, consequently suppressing ferroptosis. Subsequent reconstitution of DHCR7 abolished 7-DHC accumulation and res","journal":"Life Metabolism","year":2024,"id":434923,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":49720,"name":"Guido Kroemer","orcid":"0000-0002-9334-4405","position":1,"is_corresponding":false},{"id":103781,"name":"Daolin Tang","orcid":"0000-0002-1903-6180","position":2,"is_corresponding":false},{"id":910059,"name":"Ruoxi Zhang","orcid":"0000-0003-2538-1877","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T01:59:58.582186Z","pmid":"38523816","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":[]}