S100A8/A9 in recurrent pregnancy loss: Pathogenic mechanisms and therapeutic potential

S100A8 and S100A9 belong to the S100 calcium-binding protein family. They are primarily expressed in myeloid cells such as neutrophils, monocytes and macrophages. Recent studies have revealed that S100A8/A9 plays a critical role in recurrent pregnancy loss (RPL). However, its function shows significant dose-tissue-temporal dependency. Clinical studies have confirmed that S100A8/A9 expression is significantly upregulated in the decidual tissue of RPL patients (80% of cases show high expression). It is mainly localized to maternal-derived myeloid immune cells. In contrast, serum levels lack diagnostic value, indicating that its effects are primarily localized to tissues. Mechanistically, S100A8/A9 acts as damage-associated molecular patterns (DAMPs). It can: (1) activate the TLR4/RAGE-NF-κB/MAPK pathway to induce inflammatory cascades; (2) activate the NLRP3 inflammasome to induce pyroptosis; (3) promote platelet activation and microthrombus formation via the GPIbα receptor; and (4) dysregulate immune cell function, thereby disrupting maternal-fetal immune tolerance. However, S100A8 gene knockout has been shown to lead to complete embryo resorption, suggesting that its physiological expression is indispensable. Therefore, in-depth investigation of the dual role and precise regulatory mechanisms of S100A8/A9 in RPL is important and will help elucidate disease pathogenesis and develop novel diagnostic tools and therapeutic strategies. This article reviews the role, mechanisms, and translational prospects of S100A8/A9 in RPL, aiming to provide new perspectives for precision prevention and treatment.