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We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against\n                    <jats:italic>Asns<\/jats:italic>\n                    in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4\u2013ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with\n                    <jats:italic>Asns<\/jats:italic>\n                    -ASO or\n                    <jats:italic>Scr<\/jats:italic>\n                    -ASO revealed major changes in the mutants, several of which are rescued by\n                    <jats:italic>Asns<\/jats:italic>\n                    silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by\n                    <jats:italic>Asns<\/jats:italic>\n                    -ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with\n                    <jats:italic>Asns<\/jats:italic>\n                    -ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.\n                  <\/jats:p>","DOI":"10.1038\/s44321-024-00071-9","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T11:01:29Z","timestamp":1714388489000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3911-9944","authenticated-orcid":false,"given":"Sara","family":"Clerici","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5391-3378","authenticated-orcid":false,"given":"Christine","family":"Podrini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7756-6788","authenticated-orcid":false,"given":"Davide","family":"Stefanoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Distefano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7350-3069","authenticated-orcid":false,"given":"Laura","family":"Cassina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Elena","family":"Steidl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Tronci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4589-9377","authenticated-orcid":false,"given":"Tamara","family":"Canu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Chiaravalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Spies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"3rd","given":"Thomas A","family":"Bell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana SH","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-6490","authenticated-orcid":false,"given":"Angelo","family":"D\u2019Alessandro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3293-7397","authenticated-orcid":false,"given":"Christian","family":"Frezza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4842-6556","authenticated-orcid":false,"given":"Angela","family":"Bachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4704-4006","authenticated-orcid":false,"given":"Alessandra","family":"Boletta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,29]]},"reference":[{"key":"71_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-84609-8","volume":"11","author":"MM Baliga","year":"2021","unstructured":"Baliga MM, Klawitter J, Christians U, Hopp K, Chonchol M, Gitomer BY, Cadnapaphornchai MA, Klawitter J (2021) Metabolic profiling in children and young adults with autosomal dominant polycystic kidney disease. 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