SUSD2 suppresses colorectal cancer progression by activating NF-κB pathway to regulate NOX4-mediated oxidative stress

Sushi domain-containing protein 2 (SUSD2) is a transmembrane protein with context-dependent roles in cancer, but its function and mechanism in colorectal cancer (CRC) remain unclear. This study aimed to investigate the role of SUSD2 in CRC progression and its underlying molecular mechanism. Analysis of TCGA dataset revealed that SUSD2 was significantly downregulated in CRC tissues, and low SUSD2 expression correlated with poor patient survival. Functional experiments demonstrated that SUSD2 overexpression suppressed CRC cell proliferation, migration, and invasion, promoted apoptosis in vitro, and inhibited tumor growth in a xenograft mouse model. Mechanistically, SUSD2 activated the NF-κB pathway, leading to p65 nuclear translocation and transcriptional upregulation of NOX4, which induced lethal oxidative stress characterized by increased reactive oxygen species, malondialdehyde, and mitochondrial superoxide. Knockdown of NOX4 rescued SUSD2-mediated phenotypic effects, and pharmacological inhibition of NF-κB abrogated SUSD2-induced NOX4 upregulation, confirming that NOX4 functions downstream of NF-κB in this axis. Collectively, these findings establish SUSD2 as a tumor suppressor in CRC and an independent prognostic biomarker. The SUSD2/NF-κB/NOX4 axis represents a critical regulatory pathway that constrains CRC progression and offers a potential therapeutic vulnerability.