IFN-I 诱导的 LAP3 通过靶向 HSD17B10/PE 通路抑制滋养层线粒体自噬，促进胚胎吸收。

Abstract

Type I interferon (IFN-I) is required for successful pregnancy; however, prolonged and excessive IFN-I activation impairs fetal development, and pathogenic interferon-stimulated genes (ISGs) mediating these effects remain incompletely elucidated. In this study, we demonstrate that viral infections and excessive IFN-I signaling significantly upregulate leucine aminopeptidase 3 (LAP3). Elevated LAP3 expression suppresses the proliferation and migration of trophoblast cells, whereas LAP3 deficiency significantly attenuates poly(I:C)-induced embryo resorption in mice. LAP3 deficiency is associated with changes in mitophagy-associated pathways involving phosphatidylethanolamine (PE) metabolism and hydroxysteroid 17-beta dehydrogenase 10 (HSD17B10) regulation. Mechanistically, LAP3 interacts with polyadenylate-binding protein cytoplasmic 1 (PABPC1) and regulates HSD17B10 protein stability. Collectively, our findings indicate that viral infections and excessive IFN-I signaling increase LAP3 expression, which is associated with reduced PE levels and altered HSD17B10 regulation. These alterations are associated with impaired trophoblast mitochondrial homeostasis and may contribute to pregnancy loss. Our study provides novel mechanistic insights and identifies LAP3 as a potential therapeutic target for mitigating such pathological conditions.