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

Xinyuan Zhao1, Xin Liao2, Yunfan Lin1

  • 1Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou 510280, China.

Acta Pharmaceutica Sinica. B
|August 13, 2026
PubMed

Insights

The PLOD1-PFKP-glycolysis axis drives cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) by enhancing glycolysis and promoting tumor plasticity. Targeting this axis can restore sensitivity to chemotherapy.

Area of Science:

  • Biochemistry
  • Molecular Oncology
  • Cancer Metabolism

Background:

  • Cisplatin is a key treatment for head and neck squamous cell carcinoma (HNSCC).
  • Acquired cisplatin resistance limits its therapeutic effectiveness in HNSCC.
  • Understanding resistance mechanisms is crucial for improving HNSCC treatment outcomes.

Purpose of the Study:

  • To identify key molecular drivers of cisplatin resistance in HNSCC.
  • To elucidate the mechanism by which PLOD1 contributes to chemoresistance.
  • To evaluate targeting the PLOD1-PFKP-glycolysis axis as a therapeutic strategy for HNSCC.

Main Methods:

  • Analysis of PLOD1 expression in cisplatin-resistant HNSCC tumors.
  • Investigating the interaction between PLOD1, PFKP, AKT, and HSP90.
  • Assessing the impact of PLOD1 modulation on glycolysis, EMT, stemness, and TGF-β signaling.
  • Evaluating the efficacy of PLOD1 silencing in preclinical HNSCC models.

Main Results:

  • PLOD1 is upregulated in cisplatin-resistant HNSCC and linked to poor prognosis.
  • PLOD1 stabilizes PFKP via AKT-mediated phosphorylation, increasing glycolytic flux.
  • This axis promotes epithelial-mesenchymal transition (EMT), stem-like properties, and activates TGF-β signaling.
  • PLOD1 silencing reverses resistance, inhibits tumor growth, and reduces metastasis.

Conclusions:

  • The PLOD1-PFKP-glycolysis axis is a central driver of cisplatin resistance in HNSCC.
  • This axis integrates metabolic and epigenetic changes to enhance tumor plasticity.
  • Targeting the PLOD1-PFKP-glycolysis axis offers a novel strategy to overcome HNSCC chemoresistance.
Keywords:
Cisplatin resistanceEpigenetic regulationGlycolysisHead and neck squamous cell carcinomaMetabolic reprogrammingPFKPPLOD1TGFBR2

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