A20 Facilitates Oxaliplatin Sensitivity in Colorectal Cancer Through Monoubiquitylation of IKK‐β

The ubiquitin-editing enzyme A20 is essential for maintaining inflammatory homeostasis, yet its role in chemoresistance remains unclear. To investigate how A20 regulates oxaliplatin resistance in colorectal cancer (CRC), with a focus on A20-mediated IKK-β 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-NACRT) or capecitabine-only neoadjuvant chemoradiotherapy (non-oxaliplatin-NACRT). Preoperative biopsy and matched surgical specimens are evaluated by immunohistochemistry to determine A20's association with oxaliplatin response. In oxaliplatin-NACRT group, patients achieving pathological complete response (pCR) displayed lower A20 expression than non-pCR patients, whereas no difference is observed in non-oxaliplatin-NACRT 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-β via its fourth zinc-finger domain, promoting IKK-β degradation and suppressing NF-κB nuclear translocation. A20 knockdown or expression of the IKK-β K163R mutant induced oxaliplatin resistance in mouse xenografts. Clinically, A20 expression are negatively associated with IKK-β and its downstream targets. A20 depletion promotes oxaliplatin resistance in CRC by stabilizing IKK-β. the results uncover an essential role of the A20-IKK-β axis in oxaliplatin resistance of CRC.