Collectively, our findings demonstrate that MIR4435-2HG promotes USF1 succinylation and stabilization, leading to the formation of a MIR4435-2HG - USF1-AKT - CREB1 signalling loop that drives epithelial - mesenchymal transition and facilitates the invasive and metastatic potential of HNSCC cells. Here, USF1 is linked to head and neck squamous cell carcinoma.