Emodin Attenuates LPS‐Induced Acute Lung Injury Through Suppression of the LCK/Fyn/AKT/p38 Signaling Axis: Integrated Transcriptomic and Experimental Evidence
Yaqiu Guo, Yunting Pang, Luyao Yang, Yanan Liang, Wei Liu, Jingxuan Guo, Tao ZhaoBackground
Sepsis‐associated acute lung injury (ALI) is characterized by intense inflammatory signaling and epithelial injury, yet effective pathway‐directed therapies remain limited. Emodin has anti‐inflammatory and tissue‐protective properties, but the signaling mechanisms relevant to inflammatory lung injury are not fully defined.
Methods
Sepsis‐associated genes were identified in GSE65682 by differential expression analysis and weighted gene co‐expression network analysis (WGCNA). Candidate emodin‐associated targets were integrated with the sepsis gene set and examined by protein–protein interaction analysis, functional enrichment, four machine‐learning models, and single‐cell RNA sequencing of GSE167363. Key predictions were then evaluated in an LPS‐induced ALI mouse model and in LPS‐stimulated A549 cells.
Results
We identified 318 sepsis‐associated genes and 34 candidate therapeutic targets. LCK , MAPK14 , and FYN were central network nodes; internally cross‐validated models showed near‐perfect discrimination but were interpreted as exploratory, and single‐cell analysis localized TSPO and UPP1 mainly to myeloid populations. In mice, emodin improved lung histopathology and reduced the inflammation score without a monotonic dose response; TNF‐α was broadly reduced, IL‐6 responses were dose selective, and IL‐1β showed no consistent change. In A549 cells, emodin was noncytotoxic, reduced LPS‐induced caspase‐3 activity, and lowered EdU positivity at low and medium doses. Emodin also reduced selected candidate‐gene transcripts and LCK/Fyn/AKT/p38 phosphorylation. MAPK14 silencing decreased p38 protein and the LPS‐associated inflammation score.
Conclusions
Emodin attenuated LPS‐induced inflammatory lung injury and cellular stress in association with reduced LCK/Fyn/AKT/p38 signaling. The findings support a contributory role for MAPK14 /p38, while direct target engagement and the translational relevance of computationally prioritized candidates require independent validation.