The Role of High Mobility Group Box 1 in Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL) is a complex reproductive disorder affecting 2%–5% of couples, with nearly half of cases remaining unexplained despite extensive clinical evaluation. Increasing evidence implicates immune dysregulation and persistent inflammation at the maternal–foetal interface as central mechanisms underlying unexplained RPL. High mobility group box 1 (HMGB1), a nuclear protein that functions extracellularly as a damage-associated molecular pattern, has emerged as a critical mediator linking cellular stress, inflammation and immune imbalance in early pregnancy. Under physiological conditions, tightly regulated HMGB1 signalling supports implantation, trophoblast differentiation, placental development and maternal–foetal immune tolerance. However, sustained or excessive HMGB1 release shifts the uterine microenvironment towards pathological inflammation through activation of pattern-recognition receptors, including Toll-like receptors and the receptor for advanced glycation end products, leading to downstream activation of nuclear factor-[Formula: see text]B and mitogen-activated protein kinase pathways. This dysregulation promotes cytokine imbalance, immune cell activation, trophoblast apoptosis, aberrant placentation and placental insufficiency, ultimately contributing to pregnancy failure. This narrative review synthesises current clinical and experimental evidence on the role of HMGB1 in RPL, with particular emphasis on its immunological and inflammatory mechanisms at the maternal–foetal interface. We highlight HMGB1’s dual, context-dependent role in pregnancy maintenance and pathology, summarise its interactions with immune signalling pathways and cell death mechanisms and discuss emerging clinical observations supporting its utility as a biomarker of immune-mediated RPL. Finally, we explore therapeutic perspectives targeting HMGB1-mediated pathways and identify key research gaps. Understanding the regulatory balance of HMGB1 signalling may facilitate the development of targeted diagnostic and therapeutic strategies, offering new avenues for the personalised management of RPL.