KAT2A promotes NLRP3-mediated trophoblast pyroptosis in preeclampsia by the succinylation

Background and objective: Trophoblast Pyroptosis contributes to the pathogenesis of preeclampsia (PE). Succinylation is a posttranslational modification that is involved in the progression of various diseases. This study aimed to explore the role of the succinyltransferase KAT2A in PE by evaluating its impact on Pyroptosis.

Methods: Rats were injected with N-nitro-L-arginine methyl ester to generate a PE model, and blood pressure was detected. HTR-8/SVneo cells were treated with hypoxia and reoxygenation, and Pyroptosis was evaluated by flow cytometry and western blotting. The mechanism was assessed using immunoprecipitation, cycloheximide chase experiment, and western blotting.

Results: KAT2A was highly expressed in the placentas of PE rats. Knockdown of KAT2A inhibited Pyroptosis of the HTR-8/SVneo cell model in vitro and ameliorated blood pressure and Pyroptosis in the placenta in vivo. Additionally, KAT2A promoted the succinylation of NLRP3 at the lysine (K)21 site, and mutation of NLRP3 at this site reduced its stability. Moreover, overexpression of NLRP3 counteracted the inhibition of Pyroptosis caused by KAT2A knockdown.

Conclusion: Silencing of KAT2A inhibits trophoblast Pyroptosis by downregulating NLRP3 expression, thereby alleviating PE. Mechanistically, KAT2A stabilizes NLRP3 by facilitating its succinylation at K21 site. These findings suggest that KAT2A may be a promising target for the treatment of PE.

KAT2A; NLRP3; preeclampsia; succinylation; trophoblast pyroptosis.