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

Zhang, Y.; Ling, N.; Wu, M.; Zeng, L.; Chen, B.; Liu, W.; Li, Z.; Li, X.; Mao, Y.; Huang, Y.; Zhou, S.; Wan, S.; Wang, H.; Tu, Y.; Wu, J.; Ye, M.; Wu, W.

doi:10.64898/2026.07.27.741014

bioRxiv · 10.64898/2026.07.27.741014

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

Zhang, Y.·Ling, N.·Wu, M.·Zeng, L.·Chen, B.·Liu, W.·Li, Z.·Li, X.·Mao, Y.·Huang, Y.·Zhou, S.·Wan, S.·Wang, H.·Tu, Y.·Wu, J.·Ye, M.·Wu, W.

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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.

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Zhang, Y., Ling, N., Wu, M., Zeng, L., Chen, B., Liu, W., Li, Z., Li, X., Mao, Y., Huang, Y., Zhou, S., Wan, S., Wang, H., Tu, Y., Wu, J., Ye, M., Wu, W.. 2026-07-30. Immunometabolic Reprogramming by Thyroid-Stimulating Antibodies Drives Orbital Adipogenesis via Histone Lactylation in Thyroid Eye Disease. https://doi.org/10.64898/2026.07.27.741014

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