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Cancer stem cells (CSCs) play central roles in drug resistance and CRC recurrence. Therefore, targeting the epigenetic mechanisms that sustain CSC properties is a promising therapeutic approach. In this study, we report the efficacy of a treatment strategy with the potential to overcome chemotherapy resistance that involves administering the well-known antiepileptic drug and epigenetic agent valproic acid (VPA) and the standard chemotherapy regimen of oxaliplatin\/fluoropyrimidine to wild-type CSCs and CSCs with BRAF and RAS mutations in enriched primary spheroid cultures. Notably, we demonstrated that VPA plus chemotherapy was more effective than other epigenetic drug-chemotherapy combinations by inhibiting cell proliferation and clonogenic growth and by inducing apoptosis and DNA damage. Mechanistically, proteomic analysis demonstrated that VPA induced CSC differentiation through the critical target of VPA, \u03b2-Catenin. Indeed, VPA promoted the proteasome-dependent degradation of \u03b2-Catenin by enhancing its binding to the E2 ubiquitin-conjugating enzyme UBE2a, leading to marked reductions in nuclear and cytoplasmic \u03b2-Catenin levels and subsequently decreasing \u03b2-Catenin\/TCF-LEF target promoter activation. These effects were confirmed in three in vivo CRC xenograft models, including a syngeneic CT26 immunocompetent mouse model, where VPA combined with oxaliplatin\/capecitabine chemotherapy and anti-VEGF therapy, a standard first-line treatment for mCRC, significantly suppressed tumor growth and prolonged survival with minimal toxicity. Proteomic analysis of tumor tissues from in vivo CRC models confirmed the VPA-mediated downregulation of CSC markers and \u03b2-Catenin.<\/jats:p>","DOI":"10.1038\/s41419-025-07902-8","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T15:47:01Z","timestamp":1754063221000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Valproic acid improves the efficacy of oxaliplatin\/fluoropyrimidine-based chemotherapy by targeting cancer stem cell via \u03b2-Catenin modulation in colorectal cancer"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9621-0939","authenticated-orcid":false,"given":"Maria Serena","family":"Roca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Lombardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Testa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Iannelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Grumetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Moccia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Barile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Addi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Memoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Leone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6217-2161","authenticated-orcid":false,"given":"Simone","family":"Di Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1016-9059","authenticated-orcid":false,"given":"Giorgio","family":"Stassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Avallone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bruzzese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biagio","family":"Pucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6330-6053","authenticated-orcid":false,"given":"Alfredo","family":"Budillon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6223-7845","authenticated-orcid":false,"given":"Elena","family":"Di Gennaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"7902_CR1","first-page":"12","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. 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PLoS Biol. 2020;18:e3000411.","journal-title":"PLoS Biol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07902-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07902-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07902-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T12:51:18Z","timestamp":1757335878000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07902-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,1]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7902"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07902-8","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,1]]},"assertion":[{"value":"27 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 August 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were carried out in accordance with relevant guidelines and regulations. Sphere cells were kindly provided by the Stassi G Laboratory and isolated from CRC patients undergoing colon resection, in accordance with the ethical standards regarding Human Experimentation (authorization CE9\/2015, Policlinico Paolo Giaccone, Palermo). Informed consent was obtained from all subjects involved in the study. All animal procedures were performed in accordance with ARRIVE guidelines [\n                      \n                      ] (European directive 2010\/63\/UE and Italian Law\u2014Directive 2010\/63\/EU and DL 26\/2014) and were approved by the appropriate institutional review board (no. 377\/2018-PR).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"583"}}