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.

Virus-induced neonatal liver failure remains a critical health challenge with poorly understood mechanisms. This study employed a comprehensive approach to investigate the pathological role of phosphodiesterase 4B (PDE4B) in rotavirus-associated liver injury. In this study, we utilized a mouse model of virus-induced liver injury model through the intraperitoneal injection of rhesus rotavirus (RRV) into newborn BALB/c mice, and applied dipyridamole as treatment strategy. We performed single cell sequencing and high-resolution immune landscape exploration on liver samples (n = 3 per group) from control (50 μL phosphate-buffered saline [PBS]), RRV-infected mice (50 μL PBS with 1.5 × 10⁶ plaque-forming units of RRV on the first day), and dipyridamole-treated mice (RRV-injected mice with 2.5 mg/kg/day dipyridamole for 12 days). We showed that dipyridamole-mediated inhibition of phosphodiesterases (PDEs) restored the differentiation trajectory of neutrophils by suppressing their activation and promoting clearance. In addition, dipyridamole suppressed the activation of autoreactive B cells and cytotoxic lymphocytes, which collectively ameliorated liver pathology and improved neonatal survival following RRV infection. In summary, we demonstrated that inhibition of phosphodiesterase signaling alleviates liver failure in murine models of neonatal rotavirus infection, thereby revealing a candidate strategy to treat rotavirus-associated diseases in neonates.