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

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.