Synergistic DBNDD1/GDF15 signaling activates the NFkB pathway to promote colorectal cancer progression

Colorectal cancer (CRC) is a high-mortality gastrointestinal tract malignancy whose pathogenesis and molecular drivers remain incompletely defined.This study aimed to identify novel key genes governing CRC pathogenesis and progression to improve detection and prognosis. We integrated 585 CRC samples and 329 normal samples from the Gene Expression Omnibus (GEO) database, constructing a weighted gene co-expression network (WGCNA) across a total number of 24,069 genes.Subsequently, five modules associated with CRC were identified via WGCNA. Functional enrichment analysis revealed these modules were significantly enriched in MAPK signaling and cholesterol metabolism pathways. Using LASSO regression, we distilled 13 hub genes (ABCB5, AOC1, ARHGAP44, CACNG3, DBNDD1, GAS7, GTF2IRD1, PRSS22, SCN4A, TTC22, DLX6, PDK4, and SLC13A2) from these modules. TCGA survival analysis demonstrated that elevated expression of ARHGAP44, CACNG3, DBNDD1, AOC1, and ABCB5 correlated with poor overall survival in CRC patients..Machine learning validation confirmed the robustness of these genetic predictors. Experimental analyses validated DBNDD1 and GDF15 upregulation in CRC, which orchestrates constitutive NF-kB activation through DBNDD1-dependent GDF15 induction.DBNDD1 knockdown suppressed proliferation, migration, and invasion in vitro (DLD1/HCT116 cells), concomitant with diminished GDF15 expression and reduced p-NFkB p65/p-IkB signaling.Consistently, DBNDD1 knockdown attenuated tumor growth in vivo, confirming its non-redundant oncogenic role.Collectively, we decipher a linear DBNDD1-GDF15-NF-kB signaling cascade driving CRC progression, thereby nominating DBNDD1 as an actionable therapeutic target for biomarker-guided precision intervention.