APOC1 deficiency disrupts M1/M2 macrophage balance via the ferroptosis and suppresses trophoblast invasion in recurrent pregnancy loss

Abstract

The maternal–fetal interface requires tightly regulated immune homeostasis for successful pregnancy. Dysregulation of macrophage polarization and trophoblast invasion is implicated in recurrent pregnancy loss (RPL). However, the molecular mechanisms by which macrophage dysfunction contributes to miscarriage remain incompletely understood. In this study, we investigated the role of apolipoprotein C1 (APOC1) in regulating macrophage polarization and trophoblast invasion using human samples from RPL patients, as well as cellular and macrophage-specific Apoc1-deficient mouse models. We observed that APOC1 expression was significantly decreased in macrophages from RPL patients compared to normal controls. APOC1 deficiency inhibits the NRF2/HO-1 signaling pathway, triggering ferroptosis and subsequent cGAS/STING activation, which drove a phenotypic switch of macrophages from an M2-dominant to an M1-dominant pro-inflammatory state. Furthermore, APOC1 deficiency-induced macrophage polarization imbalance led to excessive IL-1β production, which contributed to the suppression of trophoblast invasion. In vivo experiments further confirmed that macrophage-specific Apoc1 deficiency led to an aberrant immune microenvironment at the maternal–fetal interface and impaired placental invasion, ultimately resulting in miscarriage. Collectively, our findings suggest a novel APOC1/ferroptosis/cGAS/STING signaling cascade that may drive aberrant macrophage polarization in RPL. The resulting polarization imbalance, leading to increased inflammatory cytokine production, links macrophage dysfunction to trophoblast impairment and may contribute to miscarriage. Targeting this signaling axis to restore macrophage polarization balance may represent a promising therapeutic strategy for preventing miscarriage and other pregnancy complications associated with excessive inflammation.