An Oxidized Mogrol Derivative Alleviates LPS-Induced Acute Lung Injury in Association with Reduced NLRP3 Inflammasome-Associated Inflammatory Responses in Mice

Acute lung injury (ALI) is a severe inflammatory pulmonary disorder with high morbidity and limited treatment options available in clinical settings. Mogrosides, natural products derived from Siraitia grosvenorii, have been shown to exhibit protective effects against ALI, but structural optimization of their aglycone moiety, mogrol, may provide opportunities to improve pharmacological efficacy. In this study, oxidized mogrol derivatives (MG-COOH and MG-CHO) were synthesized, and their anti-inflammatory activities were initially compared with those of natural mogrosides in lipopolysaccharide (LPS)-stimulated MH-S cells. MG-COOH exhibited pronounced anti-inflammatory activity and was designated for comprehensive analysis of its protective potential and underlying mechanisms in the LPS-induced ALI model. MG-COOH effectively alleviated LPS-induced injury in lung, decreased pro-inflammatory cytokine release, and reduced oxidative stress, showing a tendency toward greater efficacy relative to natural mogrosides at equimolar doses. Transcriptomic analysis indicated that MG-COOH modulated genes involved in the HIF-1, JAK-STAT, MAPK, PI3K-Akt, NF-κB, NOD-like receptor, and Toll-like receptor signaling pathways. Furthermore, MG-COOH reduced the expression of NLRP3, ASC, caspase-1, and IL-1β mRNA and protein in lung. In conclusion, the oxidized mogrol derivative MG-COOH exhibits pronounced anti-ALI activity, which is associated with reduced NLRP3 inflammasome-related inflammatory responses in the lung, which serves as a pivotal node in multiple inflammatory signaling cascades.