FAK-dependent activation of src family kinase member BLK contributed to endometrial fibrosis via endoplasmic reticulum stress

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While Src family kinases (SFKs) are established mediators of some fibrotic diseases, their specific function in endometrial fibrosis is not well defined. Here, we investigated the function and underlying mechanism of B lymphoid tyrosine kinase (BLK), an SFK member, in driving endometrial fibrosis. BLK expression was analyzed in the human endometrium and mice uterus, as well as in human endometrial stromal cells (hEndoSCs). Its functional role was assessed using siBLK in TGF-β1-induced hEndoSCs and in the intrauterine adhesion (IUA) mice model with Blk knockdown (IUABlk[LKD]). BLK was overexpressed and activated in the endometrium of IUA patients, the uterus of IUA mice, and TGF-β1-induced hEndoSCs, and was accompanied by high expression of endoplasmic reticulum stress (ERS) hallmarks GRP78 and CHOP. Inhibition of BLK significantly reduced the expression levels of GRP78, CHOP, Collagen I, and α-SMA in TGF-β1-induced hEndoSCs. Endometrial fibrosis was also significantly attenuated in IUABlk[LKD] mice. Phospho-activation of BLK was found to rely on its binding with focal adhesion kinase (FAK) to form a complex, and subsequently aggravated endometrial fibrosis by regulating ERS. Our findings clarified the critical role and possible mechanism of BLK in endometrial fibrosis. BLK may serve as a promising target for treating endometrial fibrosis.

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