The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses
Authors: Lynda Bourebaba, Anna Serwotka-Suszczak, Ariadna Pielok, Mateusz Sikora, M. Mularczyk, K. Marycz
Journal: Frontiers in Endocrinology
Summary
# Editorial Summary: PTP1B Inhibition as a Novel Therapeutic Approach to Equine Metabolic Syndrome Equine metabolic syndrome represents a complex, multifactorial condition characterised by insulin resistance, systemic low-grade inflammation and laminitis risk, with emerging evidence implicating the protein tyrosine phosphatase 1B (PTP1B) enzyme as a key driver of hepatic insulin insensitivity and associated metabolic dysfunction. Bourebaba and colleagues investigated whether MSI-1436, a selective PTP1B inhibitor, could address the underlying pathophysiology by examining both ex vivo liver tissue from affected horses and clinical responses following intravenous administration of a single dose to EMS-affected animals. Treatment substantially improved systemic metabolic markers—restoring adiponectin concentrations whilst attenuating hyperinsulinaemia and hyperglycaemia—and markedly reduced pro-inflammatory cytokines (IL-1β, TNF-α, TGF-β) whilst promoting regulatory T cell activation; mechanistically, PTP1B inhibition mitigated hepatic endoplasmic reticulum (ER) stress, enhanced mitochondrial dynamics and restored autophagic flux through upregulation of HSC70, Beclin-1, MFN2 and PINK1. These findings suggest PTP1B inhibition represents a promising pharmacological strategy for addressing the interconnected inflammatory, metabolic and mitochondrial dysfunction characteristic of EMS, potentially offering a more targeted intervention than current management approaches focused primarily on diet and exercise.
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Practical Takeaways
- •MSI-1436 shows promise as a novel therapeutic approach for managing equine metabolic syndrome by addressing multiple pathogenic mechanisms simultaneously
- •Single-dose IV administration improved both metabolic markers and systemic inflammation in affected horses, suggesting potential clinical utility
- •This research provides mechanistic rationale for targeting PTP1B inhibition in EMS management, though further clinical trials are needed before routine practice implementation
Key Findings
- •MSI-1436 (PTP1B inhibitor) restored normal adiponectin levels and reduced hyperinsulinemia and hyperglycemia in EMS horses
- •Treatment significantly reduced pro-inflammatory markers (IL-1β, TNF-α, TGF-β) and activated regulatory T cells
- •MSI-1436 mitigated liver endoplasmic reticulum stress and improved mitochondrial dynamics through enhanced autophagy regulation
- •Ex vivo liver explant treatment upregulated autophagy markers (HSC70, Beclin-1) and mitophagy markers (MFN2, PINK1) while suppressing ER stress mediators