c-Fos Mediates Preeclampsia Through p-AMPK/Detyrosinated Tubulin Pathway
Yihong Huang, Shanshan Zhao, Chumei Zeng, Shaole Shi, Zhuyu Li, Lixia Shen, Huizhen Geng, Zilian Wang, Dongyu WangBACKGROUND:
Preeclampsia is a systemic disorder unique to pregnancy that is associated with trophoblast dysfunction. Although the c-Fos (FBJ osteosarcoma oncogene) is essential for placental development, its mechanistic role in preeclampsia remains unclear.
METHODS:
We identified c-Fos as a hub gene through an analysis of cell-free RNA from maternal plasma and single-cell RNA sequencing of preeclamptic placentas. We assessed c-Fos expression in the placenta and plasma and examined its correlation with lipids. Functional changes upon the viral modulation of c-Fos in trophoblast cells were evaluated. Untargeted lipidomics and RNA sequencing were conducted to uncover the downstream mechanisms, and the findings were validated in trophoblast cells and a preeclampsia-like murine model.
RESULTS:
c-Fos expression was decreased in maternal peripheral plasma from early to mid-pregnancy and in the placenta of preeclampsia patients. Furthermore, c-Fos expression levels were negatively correlated with neutral lipid accumulation. c-Fos deficiency impaired trophoblast invasion, proliferation, and syncytialization while promoting apoptosis. Reduced c-Fos expression also led to lipid droplet aggregation and mitochondrial dysfunction. Mechanistically, c-Fos silencing inhibited the p-AMPK (phosphorylated AMP-activated protein kinase)/detyrosinated tubulin pathway, disrupting lipid droplet trafficking and metabolism and promoting lipid droplet accumulation and an altered lipid profile. c-Fos deficiency induced a preeclampsia-like phenotype in mice, whereas c-Fos overexpression partially alleviated preeclampsia symptoms.
CONCLUSIONS:
c-Fos downregulation inhibits the p-AMPK/detyrosinated tubulin pathway, driving lipid droplet accumulation and consequent trophoblast dysfunction, revealing c-Fos as a potential therapeutic target for preeclampsia.