Background <p>Methyltransferase 13 (METTL13) is a methyltransferase involved in mRNA translation and could function as either oncogene or tumor suppressor in cancers, but its function and mechanism in esophageal cancer remain unknown. In this study, we revealed that METTL13 promotes esophageal squamous cell carcinoma (ESCC) progression through methylation-dependent mRNA translation.</p> Methods <p>METTL13 expression was analyzed using clinical database The Cancer Genome Atlas (TCGA) and ESCC samples collected. In vitro assays including CCK-8, colony formation, transwell and sphere-forming were utilized to determine the oncogenic functions of METTL13. Polyribosome-bound mRNA sequencing was performed to evaluate mRNA translation efficiencies under regulation of METTL13, which were further confirmed by quantitative RT-PCR and western blot. Alterations of Oxygen Consumption Rate (OCR) and levels of metabolites involved in lipid metabolism by seahorse assay and specific kits were detected respectively in ESCCs under METTL13 knockdown. ESCC mouse models were established to evaluate the oncogenic functions of METTL13 in vivo.</p> Results <p>METTL13 is significantly up-regulated in clinical ESCC tissues and its high expression is associated with poor patient prognosis. Gain-of-function and loss-of-function assays demonstrated the critical function of METTL13 in regulation of ESCC progression in vitro and in vivo. Further mechanistic exploration has shown that METTL13 regulates ESCC by mediating the expression of Serum amyloid A1 (SAA1) at the translation level, which leads to lipid metabolism alteration. Sphere-forming assay experiments demonstrated that METTL13 plays an essential role in CSC-like properties in ESCC.</p> Conclusion <p>METTL13 plays the essential oncogenic role in ESCC by enhancing SAA1 expression at translational level, leading to aberrant lipid metabolism. Our study provides the molecular basis for development of effective therapeutic strategies for ESCC treatment.</p>