VPS4A activates glycolytic metabolism via MYO1C to promote radioresistance in ESCC.

ESCC is highly aggressive. The patients with advanced disease have a poor prognosis, making it the main type of EC in China. Glycolytic metabolic reprogramming supports the occurrence, malignant progression, and drug resistance of ESCC. This may lead to late cancer detection and treatment difficulties. However, the specific mechanisms driving this phenomenon remain a mystery. In this study, we found that VPS4A had high expression in ESCC tissues. It was an independent factor affecting patient prognosis. In vivo and in vitro experiments demonstrated that VPS4A activated glycolysis in ESCC to promote tumor malignant progression and radioresistance. Mechanistically, VPS4A upregulated MYO1C expression to enhance glycolytic metabolism in ESCC cells, increasing glucose uptake and lactate production, thereby enhancing the radioresistance of tumor. Moreover, lactate produced by glycolysis could also enhance the VPS4A and MYO1C expression. Overall, our study indicated that VPS4A is a valuable therapeutic target for ESCC, highlighting the significance of the VPS4A/MYO1C/glycolysis axis in ESCC progression.