HMGB1 as a trigger for inflammatory storms: a potential biomarker for adverse pregnancy outcomes†.

The maternal-fetal interface comprises trophoblast cells, immune cells, decidual cells, and various other cellular components that collectively contribute to the maintenance of 1immune homeostasis through the secretion of specific cytokines and hormones. Inflammation plays a crucial role in successful embryo implantation, pregnancy maintenance, and parturition; however, it also exhibits a dual role in reproduction and pregnancy. Excessive activation of inflammatory processes, conversely, may have detrimental effects on pregnancy outcomes. Research has demonstrated that elevated levels of High Mobility Group Box 1 (HMGB1) in maternal circulation correlate with negative pregnancy outcomes, including unexplained recurrent miscarriage, gestational diabetes, and preeclampsia (PE). Furthermore, HMGB1 functions by activating the NF-κB signaling pathway through its interaction with the receptor for advanced glycation end-products (RAGE) and Toll-like receptors (TLRs), which subsequently enhances the expression of downstream pro-inflammatory cytokines such as IL-18, interleukin-1 beta (IL-1β), and TNF-α, thereby contributing to adverse pregnancy outcomes. Collectively, this evidence positions HMGB1 as a potential biomarker for these negative pregnancy results. This review aims to elucidate the mechanisms by which HMGB1 acts as an inflammatory regulatory factor in various adverse pregnancy outcomes and to investigate the potential therapeutic value of HMGB1 antagonists as candidate agents for the prevention and treatment of preterm birth (PB) and inflammatory damage, thereby providing a theoretical foundation for developing intervention strategies targeting HMGB1.