Lycorine protects against inflammatory hemorrhagic skin injury via suppression of neutrophil-driven NADPH oxidase activation.

Lycorine (LYC) , an alkaloid derived from Amaryllidaceae plants, exhibits broad biological activities, including anti-inflammatory, antiviral, and antitumor effects. However, its role in inflammatory hemorrhagic skin diseases and whether LYC modulate Nicotinamide Adenine Dinucleotide Phosphate(NADPH)oxidase activation remain unclear. In this study, we demonstrate that LYC dose-dependently alleviates lipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) co-induced hemorrhagic inflammation in a murine Local Shwartzman Reaction (LSR) model. LYC treatment markedly reduced cutaneous hemorrhage, neutrophil accumulation, and inflammatory cytokine production. Neutrophil depletion with an anti-Ly6G antibody similarly mitigated skin injury, confirming neutrophils as the key effector cells driving tissue damage. We discovered that LYC inhibited neutrophil migration, reactive oxygen species(ROS)generation, and the formation of neutrophil extracellular traps (NETs). When neutrophils were stimulated by complement component C5a or TNF-α, LYC effectively suppressed AKT and p38 MAPK phosphorylation. Moreover, LYC directly bound to p47phox, a cytosolic subunit critical for NADPH oxidase activation, thereby reducing its phosphorylation and membrane translocation and inhibiting ROS production. LYC alleviates inflammatory hemorrhagic skin injury by targeting p47phox to suppress neutrophil ROS generation and NETs formation, suggesting its potential as a therapeutic candidate for infection-associated hemorrhagic disorders.