{"doi":"10.1101/2025.05.19.654298","title":"Metformin inhibits PDGF signaling to suppress hyaluronan and IL-6 production in Thyroid Eye Disease","abstract":"ABSTRACT Background Thyroid eye disease (TED) is a debilitating autoimmune disorder affecting 25-50% of patients with Graves’ disease. TED is characterized by inflammation and tissue remodeling of orbital tissues. Orbital fibroblasts (OFs) and platelet-derived growth factor (PDGF) signaling promote tissue remodeling in TED. While metformin’s therapeutic potential has been proposed in various inflammatory conditions, its role in modulating PDGF signaling in TED remains unexplored. Methods OFs were isolated from TED (n= 14) and non-TED subjects (n=4). OFs were treated with PDGFβ (25 ng/mL) and/or AMPK activators metformin (1-5 mM) and AICAR (0.4-1 mM). Hyaluronan (HA) production was assessed via agarose gel electrophoresis and ELISA. Inflammatory mediators (IL6 and IL8) were measured by ELISA. Protein expression and signaling pathways were analyzed by Western blot. Results TED OFs showed enhanced HA synthesis (∼3-fold increase) and IL6 and IL8 responses to PDGFβ. PDGFβ treatment suppressed AMPK phosphorylation in a dose-dependent manner. Metformin increased AMPK phosphorylation (3.2-fold) and decreased IL6 and IL8 production. Both metformin and AICAR attenuated PDGFβ-induced HA production (56-68% reduction), IL6 (∼50% reduction), and IL8 (∼65% reduction) production in TED OFs. Conclusions This study demonstrates that PDGFβ suppresses AMPK signaling while AMPK activation by metformin counters PDGFβ-induced responses. These findings suggest that metformin is a potential therapeutic option for TED through modulation of HA and inflammatory cytokine production.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566628,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9591,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1281645,"name":"C. Patrick","orcid":"0000-0002-3267-0733","position":1,"is_corresponding":false},{"id":494837,"name":"Elisa Roztocil","orcid":null,"position":2,"is_corresponding":false},{"id":433481,"name":"Steven E. Feldon","orcid":"0000-0003-0603-9312","position":3,"is_corresponding":false},{"id":449223,"name":"Collynn F. Woeller","orcid":"0000-0001-7197-5057","position":4,"is_corresponding":false},{"id":946606,"name":"Farha Husain","orcid":null,"position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:40.491968Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}