Aldo-Keto Reductase 1B10 (AKR1B10) Restrains Trophoblast Cell Invasion via the ERK Signaling Pathway

Trophoblast invasion is crucial for the establishment of a functional placenta. Defects in this process can cause adverse pregnancy outcomes, such as miscarriage and preeclampsia. Aldo-keto reductase family 1 member B10 (AKR1B10), a key cytoplasmic oxidoreductase that converts retinoids, retinaldehyde isoprenoids, and lipid peroxidation-derived reactive aldehydes into their corresponding alcohols, regulates cell proliferation, inflammation, and metastasis in cancers. Here, our results demonstrated that AKR1B10 is highly expressed in the ectoplacental cone (EPC) of the mouse placenta. Deficiency of AKR1B10 leads to excessive trophoblast giant cell (TGC) invasion, impaired trophoblast cell differentiation of the junctional zone, and accelerated maternal spiral artery remodeling. Mechanistically, loss of AKR1B10 suppressed extracellular regulated protein kinase (ERK) phosphorylation in both murine placentas and human HTR8/SVneo cells, further promoting HTR8 cell migration and invasion in vitro. Our findings identify AKR1B10 as a critical regulator that restrains trophoblast invasion in the placenta, suggesting it as a new therapeutic target for placental disorders.