Tofacitinib alters STAT3 signaling and leads to endometriosis lesion regression

Endometriosis is a widespread gynecologic condition affecting up to 15% of women of reproductive age. The Janus kinase/signal transducer and activator of transcription (JAK/STAT3) pathway is upregulated in endometriosis and is a therapeutic target. Here we sought to determine the effect of Tofacitinib, a JAK inhibitor in widespread clinical use, on JAK/STAT signaling in endometriosis and lesion growth. Endometriosis was surgically induced in C57BL/6 mice using homologous uterine horn transplantation. Lesions were allowed to form over 4 weeks followed by Tofacitinib (10 mg/kg) or vehicle administered by oral gavage over 4 weeks. Tofacitinib treatment in vivo led to endometriosis lesion regression and reduced adhesion burden compared to vehicle treatment. In vitro studies on Ishikawa cells showed that Tofacitinib reduced hypoxia-inducible factor 1 alpha and vascular endothelial growth factor mRNA levels at 12 and 24 h. Western blot analysis showed that Tofacitinib effectively reduced STAT3 phosphorylation in Ishikawa cells and human primary stromal and epithelial cells from eutopic endometrium of patients with and without endometriosis. This study suggests that the inhibition of JAK/STAT signaling using Tofacitinib may be a viable method for the treatment of endometriosis.

Automated summary

Tofacitinib treatment can lead to regression of lesions and reduced adhesion burden in endometriosis. In vitro studies showed that Tofacitinib reduced levels of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor mRNA. Western blot analysis demonstrated that Tofacitinib effectively reduced STAT3 phosphorylation in various types of cells.