Metabolic-epigenetic reprogramming via the PLOD1-PFKP axis drives cisplatin resistance in HNSCC.

Cisplatin remains a cornerstone of treatment for head and neck squamous cell carcinoma (HNSCC), yet its therapeutic efficacy is often undermined by acquired resistance. Here, we identify the PLOD1-PFKP-glycolysis axis as a central driver of cisplatin resistance. PLOD1 is significantly upregulated in cisplatin-resistant tumors and correlates with poor prognosis. Mechanistically, PLOD1 stabilizes the glycolytic enzyme PFKP by promoting its AKT-mediated phosphorylation at serine 386 via the HSP90-AKT complex, thereby enhancing glycolytic flux. This metabolic reprogramming facilitates stem-like properties and sustains epithelial-mesenchymal transition (EMT). Furthermore, increased intracellular acetyl-CoA levels driven by this axis promote histone H3K27 acetylation at the TGFBR2 promoter, thereby activating TGF-β signaling. Genetic depletion or nanoparticle-mediated silencing of PLOD1 reverses EMT and stemness features, restores cisplatin sensitivity, and impairs tumor growth and metastasis in vivo. These findings reveal a PLOD1-PFKP-glycolysis axis as the principal driver of cisplatin resistance, which coordinates metabolic and epigenetic alterations to promote tumor plasticity. Targeting this axis offers a promising strategy to overcome chemoresistance in HNSCC.