YTHDF2-mediated stabilization of SREBF1 promotes lipid metabolic reprogramming and ferroptosis-associated radioresistance in anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is the most aggressive endocrine malignancy and frequently resistant to radiotherapy. Lipid metabolic reprogramming has been implicated in ferroptosis evasion and therapeutic resistance in cancers; however, the specific mechanisms of lipid metabolic rewiring in regulating radioresistance in ATC remain unclear. This study employed an integrated multi-omics profiling, including RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), and RNA immunoprecipitation sequencing (RIP-seq), lipidomics profiling, and mRNA stability assays, to characterize YTHDF2- mediated regulation of metabolic pathways in ATC. Functional validation assessments were performed using Seahorse XF metabolic flux analysis, fluorescence recovery after photobleaching (FRAP) imaging, ferroptosis induction/rescue models, and radiation-exposed xenograft models. Our results demonstrated that YTHDF2 directly bound to N6-methyladenosine (m6A)-modified motifs within the 3' untranslated region (3'UTR) of SREBF1 mRNA, thereby enhancing its stability and promoting the expression of downstream lipogenic enzymes, including stearoyl-CoA desaturase-1(SCD1). This lipid remodeling increased membrane fluidity, suppressed ferroptosis, and protected cells from lipid peroxidation while sustaining mitochondrial respiration, accompanied by maintenance of cellular homeostasis, including endoplasmic reticulum integrity. Notably, reintroduction of SREBF1 in YTHDF2-deficient ATC cells restored radiotolerance and reversed ferroptotic susceptibility. Additionally, both pharmacologic and genetic inhibition of YTHDF2 significantly sensitized tumors to ionizing radiation and increased ferroptosis-associated cytotoxicity in vivo. Our findings reveal a novel regulatory YTHDF2-SREBF1 axis that links m6A-dependent post-transcriptional regulation to ferroptosis modulation through lipid metabolic remodeling. Therapeutically targeting the YTHDF2-SREBF1 pathway may represent a promising strategy to overcome radiotherapy resistance in ATC through metabolic intervention.