Metformin inhibits PDGFβ signaling to suppress hyaluronan and cytokine production in thyroid eye disease.

Thyroid eye disease (TED) is characterized by fibroblast-driven inflammation and extracellular matrix expansion, which contribute to orbital congestion and proptosis. Platelet-derived growth factor-β (PDGFβ) promotes hyaluronan (HA) synthesis and cytokine production in orbital fibroblasts (OFs); however, whether metabolic modulation can counteract this pathway is unknown. We tested whether metformin, an indirect activator of AMP-activated protein kinase (AMPK), attenuates PDGFβ signaling in TED OFs. Primary OFs from 14 TED and 4 non-TED donors were treated with PDGFβ with or without metformin or the direct AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). PDGFβ elicited markedly greater HA and cytokine responses in TED OFs than in non-TED OFs and suppressed AMPK phosphorylation. Metformin treatment restored AMPK phosphorylation, reduced HA accumulation (∼2.3-3.1-fold), and decreased IL-6 and IL-8 production. AICAR produced similar AMPK-dependent effects. Mechanistically, metformin attenuated PDGFβ-driven activation of the phosphoinositide 3-kinase (PI3K)-AKT-forkhead box O1 (FoxO1)-nuclear factor kappa B (NF-κB) axis, a pro-inflammatory and pro-survival cascade. These data identify PDGFβ-mediated AMPK suppression as a pathogenic mechanism in TED fibroblasts and demonstrate that AMPK reactivation reduces pro-fibrotic and inflammatory signals. Together, these findings support the therapeutic repurposing of metformin in TED.