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ETHNOPHARMACOLOGICAL RELEVANCE Scutellariae radix (SR) is one of the most popular traditional Chinese medicines (TCM). Crude SR (CSR) and wine-processed SR (WSR) are the two most common commercial specifications. According to the theories of TCM, wine-processing increases the inclination and direction of SR's actions, thereby strengthening its efficacy in clearing the upper-energizer lung damp heat. The pharmacological mechanism-related research on WSR for the treatment of lung disease is limited and needs to be expanded. AIM OF THE STUDY The aim of this report was to identify the relevant biological pathways by assessing changes in plasma metabolites between CSR and WSR in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model, and thus, revealed the potential mechanism of wine processing in SR. MATERIALS AND METHODS Rats with LPS-induced ALI were treated with CSR and WSR. The contents of inflammatory cytokines and histopathological examination were determined to explore the effects of CSR and WSR. Next, the metabolic profiling of rat plasma samples was performed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). Then, principal component analysis (PCA) were used to provide an overview for all of the groups and orthogonal partial least squares-discriminant analysis (OPLS-DA) was utilized to maximize the discrimination and present the differences in the metabolite between all of the groups. RESULTS WSR exhibited a more remarkable effect on improving ALI than CSR by reducing the levels of inflammatory factors, including nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8). On the basis of UPLC-QTOF-MS technology, an unequal curative effect was revealed by nontargeting metabolomics. Sixteen biomarkers were discovered in the plasma of LPS-induced rats. Pathway analysis indicated that CSR acted on ALI by regulating the abnormal sphingolipid metabolism pathways; however, an WSR-mediated cure of ALI was linked primarily to reversing the abnormality of retinol metabolism pathways and tryptophan metabolism pathways. CONCLUSIONS This report to examined the underlying wine-processing mechanism of SR from the perspective of plasma metabolites. In addition, this work provided a novel and valuable insight into interpretation of the processing mechanisms of TCM in a holistic way.