NKD1 promotes the progression and 5-FU resistance of colorectal cancer via the Wnt/β-catenin signaling.

5-Fluorouracil (5-FU) resistance continues to pose a considerable barrier in the postoperative management of advanced colorectal cancer (CRC). This study identified Naked cuticle homolog 1 (NKD1) as a key factor associated with 5-FU resistance in CRC based on sequencing data from the GEO and TCGA databases. Elevated NKD1 expression correlated with adverse clinicopathological features and poor patient survival. Functional assays revealed that NKD1 overexpression elevated the IC50 of 5-FU, promoted tumor cell proliferation, and attenuated apoptosis in both drug-treated and untreated settings. Additionally, NKD1 promoted CRC cell migration and invasion, regulated tumor stem cell markers. Mechanistically, NKD1 stabilizes DVL protein, regulates APC and FZD7, and fosters nuclear accumulation of β-catenin, initiating transcriptional programs downstream of Wnt signaling. Silencing NKD1 synergized with 5-FU to improve therapeutic efficacy in patient-derived organoid and xenograft models. These results establish NKD1 as a key regulator of CRC malignancy and chemoresistance via Wnt/β-catenin pathway activation, supporting its potential as a dual biomarker and therapeutic target in combination regimens.