HOXC9 accelerates esophageal squamous cell carcinoma progression via OTUD1-FABP5-mediated lipid metabolic reprogramming

Abstract Homeobox C9 (HOXC9) plays a critical role in tumor progression. However, its function and regulatory mechanisms in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we found that HOXC9 expression was significantly upregulated in ESCC (|log 2 FC| ≥ 2, p < 0.05) and was positively associated with poor prognosis in ESCC patients ( p = 0.032). HOXC9 promoted ESCC progression in vitro and in vivo. Mechanistically, HOXC9 directly activated ovarian tumor deubiquitinase 1 ( OTUD1 ) transcription by binding to its promoter region. This activation enhanced OTUD1-mediated fatty acid binding protein 5 (FABP5) deubiquitination, increasing FABP5 protein stability, reducing lipid droplet accumulation, and elevating glycerol and free fatty acid levels ( p < 0.05), thereby accelerating ESCC cell proliferation and migration. In addition, HOXC9-OTUD1-FABP5 signaling was closely linked to the clinicopathological grade of ESCC patients. Our study comprehensively reveals the mechanism by which HOXC9 accelerates ESCC progression, and identifies potential biomarkers and therapeutic targets for the pathogenesis and clinical treatment of ESCC.