AIM2 inflammasome-mediated cell pyroptosis regulates mitophagy to participates in high glucose-induced trophoblast cell damage.

This study aimed to elucidate the role of absent in melanoma 2 (AIM2) in high glucose (HG)-induced trophoblast injury. An in vitro gestational diabetes mellitus (GDM) model was established by exposing HTR-8/SVneo cells to 25 nM glucose, followed by AIM2 knockdown. Cell viability, apoptosis, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL), wound healing, and Transwell assays, respectively. Oxidative stress markers and inflammatory cytokines were quantified via specific assay kits. Immunofluorescence assays detected expressions of gasdermin D (GSDMD) and microtubule-associated protein 1 light chain 3B (LC3B). Furthermore, Western blot analysis was conducted to assess proteins related to mitophagy and pyroptosis. Results demonstrated a significant upregulation of AIM2 expression upon HG stimulation in HTR-8/SVneo cells. AIM2 silencing enhanced cell viability and migration, while attenuating HG-induced apoptosis, oxidative stress, and inflammatory responses. Mechanistic investigations revealed that AIM2 knockdown inhibited pyroptosis and activated mitophagy. Rescue experiments indicated that the protective effects conferred by AIM2 silencing against HG-induced trophoblast damage were reversed by the mitophagy inhibitor Mdivi-1. Collectively, these findings indicate that AIM2 silencing alleviates HG-induced trophoblast injury by regulating pyroptosis and mitophagy, suggesting AIM2 as a potential therapeutic target for GDM-related placental dysfunction.