Targeting PTP1B and DUSP4 phosphatases to Boost Tregs: A Novel Therapy for Polyendocrine Metabolic Ovarian Syndrome (PMOS) Immune Dysfunction.

Polyendocrine metabolic ovarian syndrome (PMOS), previously called polycystic ovary syndrome (PCOS) - the most common reproductive endocrinopathy in women of reproductive age, is frequently associated with chronic low-grade inflammation and immune dysregulation. Beyond hyperandrogenism and ovulatory dysfunction, women with PMOS exhibit reduced regulatory T cell (Treg) levels and impaired STAT5 phosphorylation. This study investigates the molecular basis of the defective STAT5 signalling in PMOS. No significant difference in plasma IL2 levels is observed in PMOS women versus normal subjects. Analysis of 102 PMOS patients and 102 controls reveals significantly decreased JAK2 expression alongside increased expression and activity of the phosphatases PTP1B (Protein Tyrosine Phosphatase 1B), TCPTP (T cell Protein Tyrosine Phosphatase), and DUSP4 (Dual Specificity Protein Phosphatase), in leukocytes of PMOS women. In isolated Tregs, only PTP1B and DUSP4 were significantly upregulated. DUSP4 expression positively correlates with serum testosterone and luteinizing hormone levels, linking hormonal imbalance with immune defects. Functional experiments show that silencing PTP1B and DUSP4 enhances IL2-induced Treg generation. Our collective findings identify phosphatase-mediated inhibition of STAT5 signalling as a key mechanism underlying Treg deficiency in PMOS and highlight PTP1B and DUSP4 as potential therapeutic targets to restore immune tolerance and improve reproductive outcomes.