Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, mainly due to metastatic progression. Constitutive activation of the MAPK/ERK pathway driven by KRAS or BRAF mutations fuels tumor growth and dissemination. Although NF-κB signaling is commonly considered pro-tumorigenic, accumulating evidence indicates context-dependent tumor-suppressive functions. We previously observed that IKKα deficiency enhances ERK activation and metastatic outgrowth in CRC models. Here, we investigated whether IKKα restrains MAPK signaling through transcriptional regulation of dual-specificity phosphatases (DUSPs).

Bulk RNA-seq analysis was performed in wild-type (WT) and IKKα knockout (KO) patient-derived organoids (PDOs). DUSP expression was validated by qPCR, immunohistochemistry and western blot. NF-κB dependency was assessed by TNF stimulation and IKK inhibition. Inducible DUSP1 and DUSP5 constructs were generated to evaluate ERK phosphorylation, proliferation and 3D growth in vitro. In vivo metastatic assays were conducted by intrasplenic transplantation of PDOs followed by treatment with the MEK inhibitor selumetinib. Liver metastases were analyzed by immunohistochemistry for p-ERK, Ki67 and junctional markers.

IKKα loss significantly reduced DUSP1 and DUSP5 expression, identifying them as NF-κB–dependent transcriptional targets. Reduced DUSP levels correlated with sustained ERK phosphorylation, increased proliferation and enhanced metastatic burden. Ectopic expression of DUSP1 or DUSP5 restored ERK control, decreased proliferative capacity and limited organoid growth. In vivo, IKKα-deficient tumors displayed increased metastatic outgrowth and ERK activation, both reverted by selumetinib treatment. These findings uncover a previously unrecognized IKKα–NF-κB–DUSP axis that constrains MAPK signaling and metastatic expansion.

IKKα suppresses CRC metastatic outgrowth by sustaining NF-κB–dependent expression of DUSP1 and DUSP5, thereby limiting ERK activation and proliferative expansion. MEK inhibition neutralizes the metastatic advantage of IKKα-deficient tumors, supporting combined therapeutic strategies targeting MAPK signaling in contexts of IKKα inhibition or dysfunction.