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Rare genetic disorders caused by mutations in PEX genes impair peroxisome function and cause Peroxisome Biogenesis Disorders, which are characterized by liver and neurological dysfunction, hearing and vision loss, and metabolic abnormalities. The majority of Peroxisome Biogenesis Disorders (PBDs) are caused by mutations in the gene encoding PEX1, which together with PEX6 forms a hetero-hexameric AAA-ATPase complex that drives the import of enzymes into the peroxisome lumen. One particular destabilizing mutation - PEX1\n                  <jats:sup>G843D<\/jats:sup>\n                  - results in almost 30% of all cases. Here we show that deficiencies in PEX1 lead to increased levels of the oxygen-responsive transcription factor HIF1\u03b1 in normoxia, as well as a HIF1\u03b1 transcriptional signature. The increase in HIF1\u03b1 protein was rescued by overexpression of PEX1\n                  <jats:sup>WT<\/jats:sup>\n                  , suggesting PEX1 deficiencies modulate HIF1\u03b1 signaling. The increased levels of HIF1\u03b1 were not explained by defects in the oxygen responsive degradation pathway of HIF1\u03b1 that relies on proline hydroxylase domain enzyme-dependent hydroxylation and von Hippel Lindau tumor suppressor protein-dependent ubiquitination. Instead, we found that PEX1 deficiency alters HIF1\u03b1 proteostasis by reducing degradation through a hydroxylation- and autophagy-dependent mechanism. Notably, enhancing autophagic capacity by ULK1 agonism was sufficient to reduce HIF1\u03b1 levels in PEX1 deficient cells. Lastly, we demonstrate that upon hypoxia-reoxygenation, PEX1 deficient cells are slower to reset HIF1\u03b1 levels. Our results suggest that PBD patients with PEX1 deficiency may be susceptible to dysregulation of the HIF1\u03b1 pathway, particularly in tissues where oxygen gradients are physiological or developmentally required.\n                <\/jats:p>","DOI":"10.64898\/2026.09.29.755113","type":"posted-content","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:30:24Z","timestamp":1790771424000},"source":"Crossref","is-referenced-by-count":0,"title":["Autophagy dependent HIF1\u03b1 proteostasis is compromised in models of PEX1 deficiencies"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8321-8406","authenticated-orcid":false,"given":"Soham P.","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2312-456X","authenticated-orcid":false,"given":"Sambhav","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5740-3501","authenticated-orcid":false,"given":"Milagros","family":"Esmerode","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6924-8900","authenticated-orcid":false,"given":"Henry","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4950-7967","authenticated-orcid":false,"given":"Jonathan T.","family":"Vu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Quantitative Biosciences Program, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9161-7182","authenticated-orcid":false,"given":"Connor J.","family":"Sheedy","sequence":"additional","affiliation":[{"name":"Interdisciplinary Quantitative Biosciences Program, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3122-4851","authenticated-orcid":false,"given":"Chris D.","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7999-8827","authenticated-orcid":false,"given":"Brooke M.","family":"Gardner","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100309201325000_2026.09.29.755113v1.1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00051.2021"},{"key":"2026100309201325000_2026.09.29.755113v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s00418-023-02259-5"},{"key":"2026100309201325000_2026.09.29.755113v1.3","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.bbamcr.2010.03.013","article-title":"Be different\u2014The diversity of peroxisomes in the animal kingdom","volume":"1803","year":"2010","journal-title":"Biochim. 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