Abstract: Objective To explore the effect of α1-antitrypsin deficiency(AAT)on fetal growth restriction(FGR)induced by pyroptosis of placental trophoblast scorch through NLRP3/caspase-1 pathway.Methods An FGR model was established by inducing HTR-8/SVneo cells with hypoxia/reoxygenation(H/R)in vitro.The cells were divided into the control(Con)group,Con+AAT group,H/R group,H/R+AAT group,and an additional AMPK activator(AICAR)intervention group to validate the underlying pathway.Pyroptosis was detected by flow cytometry,and the expression of related proteins were measured by Western blotting.In vivo,an FGR mouse model was induced by maternal hypoxia(10.5% O₂).The mice were divided into the normal group,FGR group,and FGR+AAT group.The weights of fetuses and placentas were measured,and immunohistochemistry was performed to analyze the expression of AAT,AMP-activated protein kinase(AMPK),and Caspase-1 in placental tissues.Results In vitro,H/R exposure significantly reduced AAT expression,elevated the p-AMPK/AMPK ratio,and increased the protein levels of NLRP3,Caspase-1,and apoptosis-associated speck-like protein containing a CARD(ASC),along with an increased pyroptosis rate.These effects were reversed by AAT supplementation,whereas AICAR blocked the protective effects of AAT.In vivo,FGR mice exhibited reduced fetal and placental weights,decreased placental efficiency,diminished placental AAT expression,elevated p-AMPK/AMPK ratio,and upregulated NLRP3 pathway-related proteins.AAT intervention improved pregnancy outcomes and downregulated the expression of these proteins.Conclusion AAT attenuates hypoxia-induced FGR by inhibiting trophoblast pyroptosis mediated through the AMPK/NLRP3/ASC/Caspase-1 signaling axis,suggesting a potential therapeutic target for FGR.

Key words: α1-antitrypsin, NLR family pyrin domain-containing protein 3, trophoblast, fetal growth restriction, pyroptosis