Fatty acid oxidation drives acetyl-CoA-dependent H3K9ac reprogramming to promote adaptive resistance to BRAFV600E inhibition in thyroid cancer.

BRAF-targeted therapy is a promising strategy for thyroid cancer. However, its efficacy is limited by drug resistance. This study elucidates the role of fatty acid oxidation (FAO) in mediating adaptive resistance to BRAFV600E inhibition (BRAFi) in thyroid cancer. Through integrated transcriptomic and metabolomic analyses, we demonstrate that BRAFi by vemurafenib (PLX4032) significantly enhances FAO in thyroid cancer cells. The pharmacological inhibition of FAO via thioridazine (Thio) synergizes with BRAFi to suppress tumor growth in vitro, in vivo and in a patient-derived organoid. Mechanistically, this metabolic shift is driven by the upregulation of PGC1α, which enhances FAO. The consequent increase in intracellular acetyl-CoA reprograms the histone H3K9 acetylation (H3K9ac) landscape, thereby epigenetically activating pro-survival genes such as RUNX1. In addition, higher expression of RUNX1 correlates with poorer prognosis in thyroid cancer. Consistently, functional studies confirm RUNX1's oncogenic role, as its knockdown reduces cell proliferation, migration, and invasion. In conclusion, our work reveals a metabolic-epigenetic axis underlying adaptive response to BRAFi and identifies RUNX1 as a novel oncogene in thyroid cancer.