Palmatine Attenuates Lipopolysaccharide-Induced Acute Lung Injury Via Suppression of NLRP3 Inflammasome Activation, Pyroptosis, and Metabolic Remodeling

Acute lung injury (ALI) is a critical condition characterized by uncontrolled inflammation, respiratory insufficiency, and tissue damage, often triggered by pneumonia or sepsis. Aberrant activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome and subsequent pyroptosis are key drivers of ALI pathogenesis. Palmatine (PAL), a naturally derived isoquinoline alkaloid with diverse pharmacological effects, was investigated for the therapeutic potential against lipopolysaccharide (LPS)-induced ALI in this study, focusing on NLRP3 inflammasome, pyroptosis, and metabolic regulation. Our findings showed that PAL significantly suppressed NLRP3 inflammasome activation and pyroptosis in LPS/adenosine triphosphate (ATP)-stimulated THP-1 macrophages and inhibited M1 macrophage polarization. In C57BL/6J mice subjected to intratracheal LPS challenge, PAL alleviated lung histopathological injury, decreased tumor necrosis factor-α, interleukin (IL)-6, IL-1β, and IL-18 levels in bronchoalveolar lavage fluid, and reduced lung wet-to-dry ratio and lung tissue myeloperoxidase activity. Transcriptomic analysis revealed that PAL markedly attenuated LPS-induced upregulation of NLRP3 and Gasdermin-D (GSDMD). PAL also downregulated the mRNA expression of Caspase-1, Apoptosis-associated speck-like protein (Asc), High-mobility group box 1 (Hmgb1), Il1b, and Il18, as well as the protein levels of cleaved Caspase-1 (p20), GSDMD-N and Caspase-11 in lung tissue. Metabolomic profiling indicated PAL-driven metabolic reprogramming involving the oxidation of branched-chain fatty acids and very long-chain fatty acids. Integrated multi-omics analysis highlighted cytosolic DNA-sensing and NOD-like receptor signaling as key pathways underlying PAL's effects. Collectively, PAL mitigates ALI by inhibiting NLRP3 inflammasome activation, suppressing pyroptosis, and reprogramming metabolism, supporting its potential as a therapeutic candidate.