S100A8/A9: key regulatory factors in programmed cell death networks and disease progression.

Programmed cell death (PCD) is a critical terminal metabolic pathway in multicellular organisms that is closely associated with various biological processes. Calprotectin (S100A8/A9), a member of the S100 protein family, plays a crucial role in regulating multiple forms of PCD. As a damage-associated molecular pattern (DAMP), S100A8/A9 binds to receptors including Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), activating downstream pathways such as nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK), reactive oxygen species (ROS), and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt). Through these pathways, S100A8/A9 mediates various cellular fate processes including apoptosis, autophagy, pyroptosis, ferroptosis, necroptosis, and PANoptosis. Intervention strategies targeting S100A8/A9 have demonstrated potential therapeutic value in inflammatory diseases and tumor models. This review summarizes the molecular mechanisms and research progress of S100A8/A9 in PCD regulation, explores its coordinated role in various cell death patterns, and discusses its application prospects as a therapeutic target, providing insights and a theoretical foundation for mechanism analysis and precise intervention in related diseases.