Metformin ameliorates trophoblastic immunometabolic disorders via attenuating TLR4/NF-κB signaling through ATXN7L3-mediated histone H2B monoubiquitination.

Background: Trophoblastic inflammation and glycometabolic reprogramming represent two hallmarks of numerous diverse placental disorders, including but not limited to preterm labor, preeclampsia, and fetal growth restriction. Recent evidence indicates that TLR4/NF-κB signaling mediate the interaction between trophoblastic inflammation and glycometabolism disturbance while pharmacologic doses of metformin (MET, 10 μM) corrected these vicious states via its suppression on this pathway. However, the underlying precise mechanism remain incompletely understood.

Methods: ATXN7L3 was identified through comprehensive proteomic screening. The oxidative phosphorylation and glycolysis were detected to evaluate the metabolic reprogramming. ELISA and adhesion experiment were used to evaluate the trophoblastic inflammation. Chromatin immunoprecipitation assay and co-immunoprecipitation assays were used to clarify the precise mechanism of MET on TLR4/NF-κB signaling.

Results: MET corrected trophoblastic glycometabolic reprogramming and attenuated excessive inflammation via ATXN7L3. Mechanistically, MET regulated the TLR4/NF-κB signaling pathway through ATXN7L3-mediated Histone H2B monoubiquitylation.

Conclusions: Our findings elucidate a novel epigenetic regulatory mechanism whereby pharmacologic doses of MET ameliorated the TLR4/NF-κB signaling-induced immunometabolic disorders in trophoblasts through ATXN7L3-mediated H2Bub1. This study exploratively elucidated a novel mechanism underlying MET's pharmacological effects and provided novel insights into its role in ameliorating placental immunometabolism and development, potentially offering a novel pharmacological strategy for treating preeclampsia, fetal growth restriction, and related obstetrical syndromes.