SDCBP competes with CBL to stabilize PES1 and promote c-Myc translation in ESCC tumorigenesis.

Syndecan-binding protein (SDCBP) has been identified as a potential prognostic biomarker in esophageal squamous cell carcinoma (ESCC) in our previous study. However, its specific interacting partners and oncogenic mechanisms remain incompletely understood. Here, we identify PES1 as a direct binding partner of SDCBP and demonstrate that SDCBP stabilizes PES1 by competitively disrupting its interaction with the E3 ubiquitin ligase CBL, thereby inhibiting PES1 ubiquitination and degradation. Stabilized PES1 enhances pre-rRNA processing and promotes c-Myc protein synthesis. In a 4-nitroquinoline 1-oxide (4NQO)-induced murine model, genetic ablation of SDCBP suppresses tumor initiation and progression. To explore its therapeutic potential, we develop cyclic RGD-modified lipid nanoparticles delivering SDCBP antisense oligonucleotides (cRGD-LNPs-SDCBP-ASO), which achieve tumor-targeted SDCBP silencing, suppress the SDCBP-PES1-c-Myc axis, and inhibit patient-derived xenograft (PDX) tumor growth without apparent toxicity. Collectively, our findings identify SDCBP as a critical regulator of ESCC progression and highlight its potential as a therapeutic target.