{"doi":"10.1101/2025.11.22.689963","title":"Krüppel-like factor 1 acts upstream of the SKN-1/Nrf transcription factors to modulate oxidative stress, lipid homeostasis and longevity","abstract":"ABSTRACT Maintenance of lipid and redox homeostasis are essential for stress resistance and longevity, but the transcriptional networks coordinating these processes remain incompletely understood. In Caenorhabditis elegans , the transcription factors SKN-1A/Nrf1 and SKN-1C/Nrf2 mediate distinct stress responses that promote proteostasis, lipid homeostasis, and oxidative stress. Here we identify the Krüppel-like factor KLF-1 as a critical upstream regulator of both SKN-1A and SKN-1C. We show that KLF-1 is required for the oxidative stress resistance and longevity of germline-deficient animals. Genetic interaction studies showed that KLF-1 acts in parallel to the lipogenic regulator Sterol regulatory element-Binding Protein 1 (SBP-1/SREBP1), whereas the related KLF-2 exerts opposing effects on lipid accumulation through SBP-1. Together, these findings place KLF-1 and KLF-2 within a transcriptional network that integrates lipid metabolism, oxidative stress responses, and aging. This work uncovers a conserved regulatory network linking KLFs and SKN-1/Nrf transcription factors in the maintenance of lipid homeostasis and longevity assurance.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":585360,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1499141,"name":"Aiden McCarty","orcid":null,"position":1,"is_corresponding":false},{"id":1260520,"name":"Ugne Kurdeikaite","orcid":null,"position":2,"is_corresponding":false},{"id":1499142,"name":"Katherine Gilmore","orcid":null,"position":3,"is_corresponding":false},{"id":1499143,"name":"Ailton Cabral","orcid":null,"position":4,"is_corresponding":false},{"id":1499144,"name":"Justin Mejia","orcid":null,"position":5,"is_corresponding":false},{"id":806194,"name":"Julia R. Barrett","orcid":null,"position":6,"is_corresponding":false},{"id":1499145,"name":"Maria La Terza","orcid":null,"position":7,"is_corresponding":false},{"id":817118,"name":"Emma Johnson","orcid":"0000-0003-0155-6476","position":8,"is_corresponding":false},{"id":518068,"name":"Allison J. Carroll","orcid":"0000-0002-3576-8808","position":9,"is_corresponding":false},{"id":570953,"name":"T. Keith Blackwell","orcid":"0000-0003-3763-9134","position":10,"is_corresponding":false},{"id":340224,"name":"Jean E. Schaffer","orcid":"0000-0002-4954-6659","position":11,"is_corresponding":false},{"id":986528,"name":"Natalie Moroz","orcid":"0000-0003-3200-9168","position":12,"is_corresponding":false},{"id":986525,"name":"Jorge Iván Castillo-Quan","orcid":"0000-0002-6324-2854","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-19T02:59:20.067334Z","pmid":"41394699","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":[]}