Targeting METTL3 Attenuates Thyroid Inflammatory Injury by Restoring Th17/Treg Balance through a YTHDC2-m6A-Dependent...

Autoimmune thyroiditis (AIT) is characterized by extensive lymphocytic infiltration and progressive destruction of thyroid follicular cells (TFCs), yet the molecular mechanisms underlying persistent thyroid injury remain poorly defined. Here, methyltransferase-like 3 (METTL3) mediated N⁶-methyladenosine (m⁶A) modification is identified as a central driver of thyroid inflammation. METTL3 expression and m⁶A levels were markedly increased in TFCs from AIT patients and EAT mice, and are positively associated with immune inflammation scores. Genetic or pharmacological inhibition of METTL3 suppressed the KDR (kinase insert domain receptor, also known as vascular endothelial growth factor receptor 2, VEGFR2)/VEGFA signaling loop, reduced inflammatory cytokine release and lymphocyte infiltration, restored Th17/Treg homeostasis, and alleviated thyroid injury. Mechanistically, ROS promoted METTL3 transcription through inhibition of SIRT1-dependent epigenetic repression, while METTL3-mediated m6A modification stabilized KDR mRNA in a YTHDC2-dependent manner. In turn, activated KDR established an autocrine-paracrine KDR/VEGFA amplification circuit that sustained inflammatory signaling. Together, these findings uncover the METTL3-KDR axis as a critical epitranscriptomic mechanism driving chronic thyroid inflammation and nominate it as a promising therapeutic target for AIT.