Integrative multi-omics analysis reveals the ameliorative effects of Taohe Chengqi decoction on sepsis-associated encephalopathy via the Lcn2–JAK2/STAT3 signaling pathway

Objective To investigate the effects of Taohe Chengqi decoction (THCQ) in a cecal ligation and puncture (CLP)-induced mouse model of sepsis-associated encephalopathy (SAE) and elucidate the underlying mechanisms through multi-omics analysis integrated with network pharmacology. Methods Sepsis was induced in mice by CLP, followed by administration of THCQ or dexamethasone. The therapeutic effects were assessed using neurobehavioral, histological, and molecular analyses (western blotting and quantitative real-time polymerase chain reaction). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for THCQ profiling. Multi-omics approaches (network pharmacology, metabolomics, and transcriptomics) combined with lipocalin 2 (Lcn2)–Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis as the mechanistic target underlying THCQ-mediated neuroprotection. Results In CLP-induced SAE mice, THCQ improved neurobehavioral deficits ( P < .001), restored blood–brain barrier integrity, attenuated neuropathological damage and apoptosis ( P < .001), and mitigated neuroinflammation ( P < .001). Multi-omics analyses identified Lcn2 (|log 2 FC| = 7.43) and linoleic acid metabolism ( P = .003 and P = .001) as core targets. THCQ downregulated Lcn2 expression ( P < .001) and suppressed JAK2/STAT3 phosphorylation. Coumermycin A1-induced Lcn2 upregulation and pathway activation were reversed by THCQ ( P < .001, P = .005, P = .019, and P = .025), confirming the Lcn2–JAK2/STAT3 axis as the central mechanism. Conclusion The protective effects of THCQ against SAE involve attenuation of neuroinflammation, preservation of blood–brain barrier integrity, and inhibition of cellular apoptosis. Collectively, findings from transcriptomics, metabolomics, and network pharmacology indicate that THCQ ameliorates SAE through modulation of the Lcn2–JAK2/STAT3 signaling axis.