Insulin resistance and SIK1 hyperactivation: implications for vascular remodeling in recurrent pregnancy loss.

Recurrent pregnancy loss (RPL) is a multifactorial condition, with nearly half of cases remaining unexplained, and maternal insulin resistance is identified as a significant contributor. This study examined the role of salt-inducible kinase 1 (SIK1) in RPL patients associated with insulin resistance using villi samples, in vitro trophoblast models, and an insulin-resistant mouse model. Our results revealed that a marked increase in miscarriage risk was observed in women with a higher value of homeostatic model assessment for insulin resistance (>2.41). SIK1 expression was elevated in the villous tissues of RPL patients with insulin resistance, as well as insulin-treated trophoblast models. Overexpression of SIK1 impaired trophoblast migration and invasion by downregulating matrix metalloproteinase-2 and matrix metalloproteinase-9 and disrupted decidual natural killer cell-mediated vascular remodeling. Cocultured decidual natural killer cells exhibited altered cytokine expression, leading to endothelial dysfunction. In vivo, insulin-resistant mice showed elevated placental SIK1 expression, reduced pregnancy success, and defective spiral artery remodeling. These findings suggest that SIK1 activation driven by insulin resistance impairs trophoblast and decidual natural killer cell functions, thereby contributing to recurrent pregnancy loss.NEW & NOTEWORTHY Insulin resistance has been clinically linked to RPL, but mechanisms at the maternal-fetal interface remain unclear. This study combines clinical villous samples, in vitro trophoblast-dNK-endothelial coculture systems, and an insulin-resistant mouse model to demonstrate that SIK1 is upregulated in RPL patients with IR and impairs trophoblast invasion and cytokine regulation and endothelial remodeling. These findings implicate SIK1 in immune-vascular dysregulation, offering a mechanistic link between maternal metabolic stress and placental vascular dysfunction.