Trophoblast aging driven by IL33 deficiency elevates recurrent pregnancy loss risk through SNAP29 lactylation-mediated autophagy impairment.

Abstract

Emerging evidence implicates premature placental senescence as a central driver of pregnancy complications, though its underlying mechanisms remain elusive. Here, we report marked downregulation of IL33 (interleukin 33) in villi from unexplained recurrent pregnancy loss (URPL) patients, concomitant with elevated trophoblast senescence. More importantly, il33 knockout mice exhibited placental senescence and impaired trophoblast invasion. Mechanistically, senescent trophoblasts displayed metabolic dysregulation - including enhanced glycolysis and lactate accumulation - which disrupted macroautophagic/autophagic flux and mitochondrial function. Lactate-induced lysine lactylation at residue K169 of SNAP29 (synaptosome associated protein 29) promoted its degradation, impairing macroautophagy/autophagy and trophoblast function, ultimately driving pregnancy loss. In interventional studies, senotherapies with metformin or dasatinib plus quercetin restored placental development and improved pregnancy outcomes in both IL33-deficient and inflammation-induced miscarriage models. Our findings establish the IL33-senescence-lactate axis as a critical pathway in URPL pathogenesis and support senomodulation as a therapeutic strategy. Abbreviations : 2-DG: 2-deoxy-D-glucose; BafA1: bafilomycin A1; CHX: cycloheximide; CTB: cytotrophoblasts; D-gal: D-galactose; EVT: extravillous trophoblasts; HDAC: histone deacetylase; H2O2: hydrogen peroxide; IL33: Interleukin 33; LPS: lipopolysaccharide; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; SNAP29: synaptosome associated protein 29; STB: syncytiotrophoblasts; UMAP: uniform manifold approximation and projection; URPL: unexplained recurrent pregnancy loss; VP: etoposide.