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These processes are associated with the dramatic changes in various proteins. Given that the maturation and activation of many proteins require proteolytic processing by proprotein convertases (PCs), we sought to explore the role of PCs in uterine activation for labor. First, we found that furin was the most dramatically increased PC member in myometrial tissues from the pregnant women after onset of labor at term. Using the model of cultured human myometrial smooth muscle cells (HMSMCs), we showed that furin inhibitor CMK, D6R treatment and furin siRNA transfection suppressed contractility. Inhibition of furin activity or interfering furin expression decreased connexin 43 (CX43), prostaglandin (PG) endoperoxide synthase\u20102 (COX\u20102) and PGF2\u03b1 receptor (FP) expression and NF\u2010\u03baB activation. In mouse model, administration of furin inhibitors prolonged gestational length. However, D6R treatment did not affect RU38486\u2010 and lipopolysaccharides (LPS)\u2010induced preterm birth. Furthermore, D6R and furin siRNA treatment reduced the release of soluble form of tumor necrosis factor (TNF)\u2010related weak inducer of apoptosis (TWEAK), while furin overexpression led to an increase in soluble TWEAK release in cultured HMSMCs. D6R treatment decreased TWEAK level in blood of pregnant mice. TWEAK treatment promoted contractility and NF\u2010\u03baB activation, while TWEAK receptor fibroblast growth factor\u2010inducible 14 (FN14) antagonist treatment inhibited contractility and NF\u2010\u03baB activation in HMSMCs. In pregnant mice, administration of FN14 antagonist prolonged gestational length. Our data suggest that furin can act as a stimulator for uterine activation for labor at term. TWEAK is one of the potential substrates which mediate furin regulation of parturition initiation.<\/jats:p>","DOI":"10.1096\/fj.202002128rr","type":"journal-article","created":{"date-parts":[[2021,4,17]],"date-time":"2021-04-17T07:02:36Z","timestamp":1618642956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Furin is involved in uterine activation for labor"],"prefix":"10.1096","volume":"35","author":[{"given":"Youyi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics Research Center for Molecular Metabolomics Xiangya Hospital Central South University Changsha China"},{"name":"Department of Physiology Second Military Medical University Shanghai China"},{"name":"Department of Gynecology and Obstetrics General Hospital of Western Theater Command of PLA Chengdu 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