The PTP1B Inhibitor Trodusquemine (MSI-1436) Improves Glucose Uptake in Equine Metabolic Syndrome Affected Liver through Anti-Inflammatory and Antifibrotic Activity
Authors: Lynda Bourebaba, Anna Serwotka-Suszczak, Nabila Bourebaba, Magdalena Zyzak, Krzysztof Marycz
Journal: International Journal of Inflammation
Summary
# Editorial Summary: PTP1B Inhibition as a Novel Therapeutic Target in Equine Metabolic Syndrome Persistent liver inflammation and fibrosis are increasingly recognised as central features of equine metabolic syndrome (EMS), contributing significantly to the insulin resistance and metabolic dysfunction these horses experience. Researchers investigated whether blocking the enzyme PTP1B using trodusquemine (MSI-1436) could reverse key pathological changes in liver tissue collected from EMS-affected horses, employing flow cytometry, gene expression analysis, and protein quantification to assess inflammatory markers, fibrotic pathways, and glucose transporter function. The inhibitor substantially reduced release of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) from affected liver and blood cells whilst simultaneously boosting anti-inflammatory responses, including increased IL-10 and IL-4 expression and enhanced regulatory T cell activation. Critically, MSI-1436 suppressed the TGF-β signalling cascade that drives liver fibrosis whilst promoting protective factors like TIMP-1, and notably improved glucose uptake by increasing functional glucose transporter-2 (Glut-2) abundance on hepatocyte membranes. These findings suggest PTP1B inhibition warrants serious consideration as a therapeutic strategy for EMS management, with potential to address the hepatic dysfunction underlying this common metabolic disorder—though the translation from ex vivo liver explants to effective clinical treatment in living horses requires further investigation.
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Practical Takeaways
- •PTP1B inhibition shows promise as a targeted approach to address the underlying metabolic dysfunction in EMS by simultaneously tackling inflammation, fibrosis, and glucose handling in the liver
- •This research suggests that future therapeutic options for EMS may move beyond symptom management (diet, exercise) toward pharmacological restoration of hepatic metabolic capacity
- •Results are currently limited to tissue culture studies; clinical efficacy and safety in live horses with EMS remain to be established in future trials
Key Findings
- •PTP1B inhibition with trodusquemine (MSI-1436) reduced proinflammatory cytokines (IL-1β, TNF-α, IL-6) in EMS-affected liver explants and peripheral blood mononuclear cells
- •MSI-1436 downregulated fibrogenic pathways by suppressing TGF-β/NOX1/4 axis and MMP-2/9 overactivation while enhancing antifibrotic mediators TIMP-1 and Smad7
- •The inhibitor increased glycosylated Glut-2 abundance on hepatocyte membranes, improving glucose uptake capacity in EMS liver tissue
- •Treatment elevated anti-inflammatory cytokines (IL-10, IL-4) and activated regulatory T cells (CD4+CD25+Foxp3+), shifting the immune profile toward resolution