RRBP1 promotes osimertinib resistance by activating fatty acid oxidation-dependent metabolic and immune reprogramming in EGFR-Mutant lung adenocarcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that improves clinical outcomes in patients with EGFR-mutant lung adenocarcinoma (LUAD); however, acquired resistance remains a major limitation. Increasing evidence suggests that metabolic reprogramming within the tumor microenvironment contributes to drug resistance, whereas the molecular mechanisms linking lipid metabolism and immune regulation remain incompletely defined. In this study, lipid metabolic remodeling in osimertinib resistance was investigated to identify resistance-associated molecular factors. By integrating single-cell RNA sequencing, bulk transcriptomic analysis, machine learning-based modeling, Mendelian randomization and whole-genome sequencing, ribosome-binding protein 1 (RRBP1) was identified as a core resistance-associated factor. Resistant tumors showed enrichment of lipid metabolism-active M2 macrophages. Mechanistic analyses showed that RRBP1 activated the sterol regulatory element-binding protein 1 (SREBP1)-carnitine palmitoyltransferase 1A (CPT1A)-fatty acid oxidation (FAO) pathway, leading to increased lipid metabolic activity in tumor cells. This metabolic shift promoted M2 macrophage polarization through lipid-dependent signaling and was associated with an immunosuppressive microenvironment and reduced osimertinib sensitivity. Pharmacological inhibition of FAO partially reversed macrophage polarization and restored drug responsiveness in resistant cells. These findings support a relationship among RRBP1, SREBP1-CPT1A-FAO-related lipid metabolic remodeling, M2 macrophage polarization and osimertinib resistance. RRBP1 and FAO-related metabolic activity may represent candidate factors for further investigation in osimertinib-resistant LUAD.