Multilayered molecular architecture orchestrating programmed cell death in mucosal barriers tissues

Mucosal barrier tissues, including the nasal, respiratory, oral, gastrointestinal, and urinogenital tract, constitute the largest interface between the host and the external environment. These surfaces are continuously exposed to pathogen infection and environmental pollutants. Disruption of mucosal barrier integrity leads to various inflammatory and infectious diseases. Emerging evidence suggests that programmed cell death (PCD) plays a crucial role in shaping the integrity of barrier and local immune responses. In recent years, rapid advances have led to the identification of multiple newly characterized PCD, including apoptosis, necroptosis, autosis, pyroptosis, PANoptosis, ferroptosis, cuproptosis, parthanatos, NETosis, disulfidptosis, entosis, anoikis, methuosis, alkaliptosis, oxeiptosis, lysozincrosis, NECSO (necrosis by sodium overload), and mitoxyperiosis. In this review, we summarize recent advances in PCD, emphasizing their morphological features, activation cascades, and regulatory mechanisms, and discuss their implications in mucosal barrier homeostasis. We further examine how dysregulated PCD contributes to epithelial dysfunction, chronic inflammation, and pathogen infection.