Immunometabolic Reprogramming by Thyroid-Stimulating Antibodies Drives Orbital Adipogenesis via Histone Lactylation in Thyroid Eye Disease

Abstract

Thyroid eye disease (TED) is conventionally viewed as an autoimmune inflammatory disorder. However, the metabolic determinants driving orbital tissue remodeling remain largely undefined. Here, we uncover a paradigm-shifting mechanism whereby thyroid-stimulating antibodies (TSAbs) instigate profound metabolic reprogramming in orbital fibroblasts (OFs), driving a switch toward glycolysis and markedly elevating lactate production via the CREB/LDHA axis. Critically, we demonstrate that this TSAbs-induced metabolic perturbation is not a mere byproduct but the principal driver of pathology. Mechanistically, lactate functions as a signaling metabolite that directly potentiates adipogenesis via histone lactylation-dependent transcriptional activation of the master adipogenic regulators PPAR{gamma} and C/EBP. Collectively, our findings underscore metabolic reprogramming as a central pathogenic mechanism in TED, whereby autoimmune cues drive disease progression through metabolic-epigenetic crosstalk. This work substantiates the paradigm of TED as an immune- metabolic disorder.