{"doi":"10.1101/2025.01.17.633664","title":"Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration","abstract":"Abstract The Sarm1 NAD + hydrolase drives neurodegeneration in many contexts, but how Sarm1 activity is regulated remains poorly defined. Using CRISPR/Cas9 screening, we found loss of VHL suppressed Sarm1-mediated cellular degeneration. VHL normally promotes O 2 -dependent constitutive ubiquitination and degradation of hypoxia-inducible factor 1 (HIF-1), but during hypoxia, HIF-1 is stabilized and regulates gene expression. We observed neuroprotection after depletion of VHL or other factors required for HIF-1 degradation, and expression of a non-ubiquitinated HIF-1 variant led to even stronger blockade of axon degeneration in mammals and Drosophila . Neuroprotection required HIF-1 DNA binding, prolonged expression, and resulted in broad gene expression changes. Unexpectedly, stabilized HIF-1 prevented the precipitous NAD + loss driven by Sarm1 activation in neurons, despite NAD + hydrolase activity being intrinsic to the Sarm1 TIR domain. Our work argues hypoxia inhibits Sarm1 activity through HIF-1 driven transcriptional changes, rendering neurons less sensitive to Sarm1-mediated neurodegeneration when in a hypoxic state. Competing interests Marc Freeman is co-founder of Nura Bio, a biotech startup pursuing novel neuroprotective therapies including SARM1 inhibition. The remaining authors declare no competing interests.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":560549,"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":0.953,"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":1331760,"name":"A. A. Avetisyan","orcid":"0000-0002-1196-8485","position":1,"is_corresponding":false},{"id":646575,"name":"Kevin Swift","orcid":"0000-0002-5601-2567","position":2,"is_corresponding":false},{"id":1196323,"name":"Ya-Chen Cheng","orcid":"0000-0001-7252-7651","position":3,"is_corresponding":false},{"id":817824,"name":"Romina Barría","orcid":"0000-0002-9154-1675","position":4,"is_corresponding":false},{"id":233471,"name":"Marc Freeman","orcid":"0000-0003-3481-3715","position":5,"is_corresponding":false},{"id":1462431,"name":"Paul Meraner","orcid":"0000-0003-0153-4680","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:55:42.883572Z","pmid":"39868134","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":[]}