{"doi":"10.1093/lifemeta/load042","title":"Hyperoxidized PRDX3 as a specific ferroptosis marker","abstract":"The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application. A recent study published in Molecular Cell has identified hyperoxidized peroxiredoxin 3 (PRDX3) as a promising marker for ferroptosis, opening up new avenues for monitoring and targeting ferroptosis in disease treatment. Ferroptosis represents a form of regulated cell death driven by disturbed iron metabolism and excessive accumulation of detrimental lipid peroxides on cellular membranes [1]. It is distinctive from other forms of regulated cell death, such as apoptosis, necroptosis, and pyroptosis, through its unique morphological, biochemical, and genetic characteristics [2]. To safeguard against the adverse effects of lipid peroxides, mammalian cells have evolved robust antioxidant systems. The principal defense mechanism against ferroptosis is the solute carrier family 7 member 11 (SLC7A11)-cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis (Fig. 1) [3]. Within this signaling axis, SLC7A11 plays a pivotal role in importing extracellular cystine, which is subsequently reduced to cysteine to synthesize intracellular GSH [4]. GPX4, acting as a phospholipid hydroperoxidase, utilizes GSH as a cofactor to catalyze the conversion of lipid peroxides into non-toxic lipid alcohols, effectively suppressing ferroptosis (Fig. 1) [3]. A variety of ferroptosis inducers (FINs) have been identified, capable of triggering potent ferroptosis in cancer cells by inhibiting either GPX4 (as exemplified by RAS-selective lethal 3 (RSL3)) or the SLC7A11-mediated cystine uptake (such as with erastin). These FINs hold significant promise in the treatment of specific types of cancer. Conversely, ferroptosis inhibitors have shown potential in treating diseases associated with excessive ferroptosis, such as ischemic organ injuries, and various degenerative diseases [2, 3]. Model depicting the hyperoxidation of PRDX3 during ferroptosis. Left panel: under normal conditions, SLC7A11-mediated cystine uptake promotes GSH biosynthesis. GSH, in turn, serves as a co-factor for GPX4 to effectively detoxify lipid peroxidation and suppress the occurrence of ferroptosis. Right panel: during ferroptotic stress, PRDX3 undergoes hyperoxidation as a result of exposure to mitochondrial lipid peroxides. Subsequently, hyperoxidized PRDX3 is translocated from the mitochondria to the plasma membrane. (It should be noted that an alternative sequence may also occur, where mitochondrial PRDX3 first relocates to the plasma membrane and then undergoes hyperoxidation there. The current study does not provide definitive evidence to distinguish between these two models.) Regardless of the sequence, the presence of hyperoxidized PRDX3 at the plasma membrane inhibits cystine uptake, thereby promoting ferroptosis. Phospholipids in red refer to lipid peroxides on cellular membranes. PRDX3, peroxiredoxin 3; GPX4, glutathione peroxidase 4; GSH, glutathione; SLC7A11, solute carrier family 7 member 11. To effectively translate ferroptosis-related treatments into clinical application, it is imperative to assess the occurrence of ferroptosis under specific pathological and physiological contexts; consequently, the discovery of markers capable of precisely identifying cells undergoing ferroptosis holds significant value. However, current lack of established biomarkers, equivalent to cleaved caspase-3 for apoptosis detection, presents a significant hurdle in the precise identification of ferroptosis, especially in tissues. For example, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), byproducts of lipid peroxidation, are frequently utilized as ferroptosis markers [2, 3]. Nevertheless, these secondary products of lipid peroxidation can also arise from other oxidative stress conditions unrelated to ferroptosis. Hence, the quest for a specific ferroptosis biomarker remains a challenging endeavor within the field of","journal":"Life Metabolism","year":2023,"id":363155,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":104623,"name":"Boyi Gan","orcid":"0000-0001-8884-6040","position":1,"is_corresponding":false},{"id":812431,"name":"Yuelong Yan","orcid":"0000-0001-8495-6445","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T01:14:28.054440Z","pmid":"38179338","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":[]}