2. Academic Validation
  3. Redox-driven FABP1/PPARγ signaling fuels peroxisomal fatty acid oxidation and confers cetuximab resistance in drug-tolerant head and neck cancer cells

Redox-driven FABP1/PPARγ signaling fuels peroxisomal fatty acid oxidation and confers cetuximab resistance in drug-tolerant head and neck cancer cells

  • Free Radic Biol Med. 2026 Mar 16:246:209-222. doi: 10.1016/j.freeradbiomed.2026.01.020.
Hang Huong Ling 1,  Chin-Sheng Huang 2,  Ming-Shou Hsieh 2,  Vijesh Kumar Yadav 3,  Iat-Hang Fong 3,  Kuang-Tai Kuo 4,  Chi-Tai Yeh 5,  Jo-Ting Tsai 6
Affiliations

Affiliations

  • 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Division of Hemato-oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Keelung and Chang Gung University, College of Medicine, Keelung, 204, Taiwan.
  • 2 Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan; School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan; Department of Dentistry and Oral Health, Taipei Medical University-Shuang Ho Hospital, New Taipei City 235, Taiwan.
  • 3 Division of Hematology and Oncology, Taipei Medical University-Shuang Ho Hospital New Taipei City, 23561, Taiwan.
  • 4 Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Medical University-Shuang Ho Hospital, New Taipei City, 235, Taiwan.
  • 5 Division of Hematology and Oncology, Taipei Medical University-Shuang Ho Hospital New Taipei City, 23561, Taiwan. Electronic address: [email protected].
  • 6 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan; Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, 110, Taiwan; Department of Radiation Oncology, Cancer Center, Taipei Medical University-Shuang Ho Hospital, New Taipei City, 23561, Taiwan. Electronic address: [email protected].
PMID: 41534570 DOI: 10.1016/j.freeradbiomed.2026.01.020
Abstract

Cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is increasingly recognized as an adaptive state driven by metabolic and redox reprogramming that enables tumor cells to tolerate sustained oxidative and immune stress. Although lipid metabolism and PPARγ signaling have been implicated in therapeutic resistance, their functional contribution to drug-tolerant persister (DTP) cells and the role of peroxisomal fatty acid oxidation (FAO) remain poorly defined. In this study, we demonstrate that a redox-driven FABP1/PPARγ axis sustains peroxisome-centered FAO, GPX4-dependent antioxidant defense, and immune suppression in cetuximab-tolerant HNSCC. FABP1 expression was markedly elevated in cetuximab-tolerant DTP cell models and resistant patient tumors. Genetic silencing or pharmacological inhibition of FABP1 using a selective small-molecule inhibitor impaired tumorsphere formation, increased intracellular Reactive Oxygen Species accumulation, and induced apoptotic cell death, accompanied by coordinated suppression of FAO-associated genes, including CPT1, ACSL family members, and acyl-CoA oxidase 1. In an orthotopic SCC9-DTP xenograft model established in NOD-SCID mice, FABP1 inhibition significantly attenuated tumor growth, disrupted metabolic-redox adaptation, and reduced tumor-associated macrophage polarization toward an immunosuppressive phenotype. Our findings identify the FABP1/PPARγ axis as a central regulator of peroxisome-centered FAO and redox buffering in cetuximab-tolerant DTP cells. Targeting FABP1 collapses this adaptive metabolic-redox program, restores vulnerability to oxidative stress, and alleviates immune suppression, highlighting peroxisomal lipid metabolism as a therapeutically actionable vulnerability in refractory HNSCC.

Keywords

Cetuximab resistance; FABP1; Fatty acid oxidation; GPX4; HNSCC; PPARγ; Peroxisome; Redox homeostasis; Tumor-associated macrophage.

Figures
Products