<i>In vivo</i>, elevated PFKP accelerated tumor progression and glycolytic metabolism through AMOTL1/YAP/Hippo signaling.<h4>Conclusions</h4>PFKP remodels tumor metabolism and drives EMT in HNSCC <i>via</i> the AMOTL1/YAP/Hippo axis, highlighting its mechanistic and prognostic significance, and suggesting its potential as a future therapeutic target. This evidence concerns the gene PFKP and head and neck squamous cell carcinoma.