The core pathophysiological mechanism of acute lung injury (ALI) is a vicious cycle of inflammation, endothelial barrier disruption, and coagulation abnormalities. Conventional single-molecule studies cannot elucidate these mechanisms at the network-regulation level. This study combined proteomics with transcriptomic validation and identified 1,596 differentially expressed proteins in a lipopolysaccharide-induced ALI model. The proteins were enriched in immune inflammation, cytoskeletal regulation, and multiple key signaling pathways. Further validation confirmed that ALI pathology begins with Casp1/Tlr2-mediated neutrophil extracellular trap formation. The process progresses via vascular glycocalyx degradation, protein homeostasis disruption, and endothelial cell programmed death. Ultimately, these changes lead to microcirculatory thrombosis, forming an ordered amplified pathogenic axis. The tyrosine kinase receptor Met and the heme metabolism–epigenetic regulation network are key regulatory nodes. These findings systematically shed light on the multilevel networked regulatory mechanisms of ALI, providing a strong theoretical foundation for targeting pathological vicious cycles and developing novel intervention strategies.