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There is no convincing evidence that APC directs degradation of other substrates. Using a reconstituted cytosolic extract-based system and complementary in vivo and cellular assays, we show that SREBP2, the master regulator of cholesterol biosynthesis, is a direct APC\u2013AXIN1 substrate. APC-dependent SREBP2 degradation is conserved in\n                  <jats:italic>Xenopus<\/jats:italic>\n                  embryos, mouse colon, and human colorectal cancer cells and restricts SREBP2 target-gene expression, cholesterol synthesis, and tissue cholesterol levels. Mechanistically, APC and AXIN1 promote SREBP2 degradation via a conserved phosphodegron, which marks SREBP2 for ubiquitination by the E3 enzyme, FBXW7. Like \u03b2-catenin, SREBP2 is stabilized by extracellular Wnt ligands; unlike \u03b2-catenin, its regulation is independent of GSK3\u03b2 and CK1\u03b1 and requires the entire APC mutational cluster region (MCR), whereas \u03b2-catenin turnover can operate with only a partial MCR. These findings define a \u03b2-catenin-independent branch of Wnt signaling that couples APC to sterol metabolism, providing a mechanistic rationale to target the mevalonate\/SREBP2 axis in APC-mutant colorectal cancer.\n                <\/jats:p>","DOI":"10.1101\/2025.10.12.681896","type":"posted-content","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T14:05:16Z","timestamp":1760450716000},"source":"Crossref","is-referenced-by-count":1,"title":["The Wnt\/APC destruction complex targets SREBP2 in a \u03b2-catenin-independent pathway to control cholesterol metabolism"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1058-7314","authenticated-orcid":false,"given":"Ahmed","family":"Rattani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9397-9534","authenticated-orcid":false,"given":"Cora","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5642-0608","authenticated-orcid":false,"given":"William V.","family":"Trim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0334-658X","authenticated-orcid":false,"given":"Esteban","family":"Garita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Imada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2315-3697","authenticated-orcid":false,"given":"Saleh","family":"Khawaled","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5208-5999","authenticated-orcid":false,"given":"Heaji","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5513-5844","authenticated-orcid":false,"given":"Jiuchun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6mer H.","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Kirschner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025112101001038000_2025.10.12.681896v2.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.016"},{"key":"2025112101001038000_2025.10.12.681896v2.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8259518"},{"key":"2025112101001038000_2025.10.12.681896v2.3","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80324-4"},{"key":"2025112101001038000_2025.10.12.681896v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.07.013"},{"key":"2025112101001038000_2025.10.12.681896v2.5","doi-asserted-by":"publisher","DOI":"10.1101\/gad.230302"},{"key":"2025112101001038000_2025.10.12.681896v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00685-2"},{"key":"2025112101001038000_2025.10.12.681896v2.7","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.12.1443"},{"key":"2025112101001038000_2025.10.12.681896v2.8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1228734"},{"key":"2025112101001038000_2025.10.12.681896v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80112-9"},{"key":"2025112101001038000_2025.10.12.681896v2.10","doi-asserted-by":"publisher","DOI":"10.1038\/382225a0"},{"key":"2025112101001038000_2025.10.12.681896v2.11","doi-asserted-by":"publisher","DOI":"10.1038\/35035124"},{"key":"2025112101001038000_2025.10.12.681896v2.12","doi-asserted-by":"publisher","DOI":"10.1038\/35035117"},{"key":"2025112101001038000_2025.10.12.681896v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81333-1"},{"key":"2025112101001038000_2025.10.12.681896v2.14","unstructured":"Zhan, T. , Rindtorff, N. & Boutros, M . 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