Acetyl-CoA carboxylase 1 knockdown promotes esophageal squamous cell carcinoma metastasis via the CXCL8-NET axis

Esophageal squamous cell carcinoma (ESCC) is associated with variable clinical outcomes, even among tumours with similar characteristics, complicating treatment. Here, we identify acetyl-CoA carboxylase 1 (ACC1), a key lipogenic enzyme, as a factor influencing this variability. Specifically, ACC1 knockdown in ESCC cells induces histone acetylation, activating c-Fos and C-X-C motif chemokine ligand 8 (CXCL8) transcription, which in turn promotes epithelial-mesenchymal transition (EMT) and enhances migration and invasion via CXCL8-C-X-C motif chemokine receptor 1/2 (CXCR1/2)-mediated PI3K/AKT and MEK/ERK signalling. Additionally, ACC1 knockdown stimulates neutrophil recruitment and neutrophil extracellular trap (NET) formation through CXCL8-dependent paracrine signalling, further enhancing tumour cell migration and invasion. In ESCC xenografts, ACC1 knockdown increases neutrophil infiltration and NET formation, accelerating metastasis. Clinically, low ACC1 expression and high CXCL8 levels are linked to poor prognosis in patients with ESCC, while NET formation further correlates with reduced survival. These findings highlight the ACC1-CXCL8-NET axis as a potential therapeutic target and prognostic marker in ESCC.