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To investigate how A20 regulates oxaliplatin resistance in colorectal cancer (CRC), with a focus on A20\u2010mediated IKK\u2010\u03b2 monoubiquitylation at K163. A prospective, randomized Phase III study is conducted in patients with locally advanced CRC who received either oxaliplatin+capecitabine neoadjuvant chemoradiotherapy (oxaliplatin\u2010NACRT) or capecitabine\u2010only neoadjuvant chemoradiotherapy (non\u2010oxaliplatin\u2010NACRT). Preoperative biopsy and matched surgical specimens are evaluated by immunohistochemistry to determine A20's association with oxaliplatin response. In oxaliplatin\u2010NACRT group, patients achieving pathological complete response (pCR) displayed lower A20 expression than non\u2010pCR patients, whereas no difference is observed in non\u2010oxaliplatin\u2010NACRT group. Two additional independent cohorts confirmed A20 downregulation in human CRC tissues, and reduced A20 expression correlated with poorer survival and oxaliplatin resistance. Mechanistically, A20 monoubiquitylates IKK\u2010\u03b2 via its fourth zinc\u2010finger domain, promoting IKK\u2010\u03b2 degradation and suppressing NF\u2010\u03baB nuclear translocation. A20 knockdown or expression of the IKK\u2010\u03b2 K163R mutant induced oxaliplatin resistance in mouse xenografts. Clinically, A20 expression are negatively associated with IKK\u2010\u03b2 and its downstream targets. A20 depletion promotes oxaliplatin resistance in CRC by stabilizing IKK\u2010\u03b2. the results uncover an essential role of the A20\u2010IKK\u2010\u03b2 axis in oxaliplatin resistance of CRC.<\/jats:p>","DOI":"10.1002\/advs.202514486","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T14:15:33Z","timestamp":1765980933000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A20 Facilitates Oxaliplatin Sensitivity in Colorectal Cancer Through Monoubiquitylation of IKK\u2010\u03b2"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0216-1604","authenticated-orcid":false,"given":"Fan","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit State Key Laboratory of Oncology in South China Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou 510060 P. 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