{"doi":"10.1101/gad.350211.122","title":"ALOX5-mediated ferroptosis acts as a distinct cell death pathway upon oxidative stress in Huntington's disease","abstract":"Although it is well established that Huntington's disease (HD) is mainly caused by polyglutamine-expanded mutant huntingtin (mHTT), the molecular mechanism of mHTT-mediated actions is not fully understood. Here, we showed that expression of the N-terminal fragment containing the expanded polyglutamine (HTTQ94) of mHTT is able to promote both the ACSL4-dependent and the ACSL4-independent ferroptosis. Surprisingly, inactivation of the ACSL4-dependent ferroptosis fails to show any effect on the life span of Huntington's disease mice. Moreover, by using RNAi-mediated screening, we identified ALOX5 as a major factor required for the ACSL4-independent ferroptosis induced by HTTQ94. Although ALOX5 is not required for the ferroptotic responses triggered by common ferroptosis inducers such as erastin, loss of ALOX5 expression abolishes HTTQ94-mediated ferroptosis upon reactive oxygen species (ROS)-induced stress. Interestingly, ALOX5 is also required for HTTQ94-mediated ferroptosis in neuronal cells upon high levels of glutamate. Mechanistically, HTTQ94 activates ALOX5-mediated ferroptosis by stabilizing FLAP, an essential cofactor of ALOX5-mediated lipoxygenase activity. Notably, inactivation of the Alox5 gene abrogates the ferroptosis activity in the striatal neurons from the HD mice; more importantly, loss of ALOX5 significantly ameliorates the pathological phenotypes and extends the life spans of these HD mice. Taken together, these results demonstrate that ALOX5 is critical for mHTT-mediated ferroptosis and suggest that ALOX5 is a potential new target for Huntington's disease.","journal":"Genes & Development","year":2023,"id":389330,"datarank":0.7091081728068512,"base_score":4.727387818712341,"endowment":4.727387818712341,"self_citation_contribution":0.7091081728068512,"citation_network_contribution":0.0,"self_endowment_contribution":0.7091081728068512,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":112,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9539,"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":805162,"name":"Zhenyi Su","orcid":"0000-0001-5557-6750","position":1,"is_corresponding":false},{"id":282933,"name":"Ning Kon","orcid":"0000-0002-5699-3780","position":2,"is_corresponding":false},{"id":618518,"name":"Bo Chu","orcid":"0000-0001-9754-2743","position":3,"is_corresponding":false},{"id":550838,"name":"Huan Li","orcid":"0000-0003-0736-9292","position":4,"is_corresponding":false},{"id":106927,"name":"Xuejun Jiang","orcid":"0000-0002-8670-3828","position":5,"is_corresponding":false},{"id":770462,"name":"Jianyuan Luo","orcid":"0000-0001-6057-2914","position":6,"is_corresponding":false},{"id":90272,"name":"Brent R. Stockwell","orcid":"0000-0002-3532-3868","position":7,"is_corresponding":false},{"id":486978,"name":"Wei Gu","orcid":"0000-0002-1641-5740","position":8,"is_corresponding":false},{"id":1159622,"name":"Shujuan Song","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:18:22.323414Z","pmid":"36921996","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":[]}