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Background Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a life-threatening condition characterized by uncontrolled inflammation and progressive fibrosis, with limited effective therapies. Kangxianhuanji Formula (KHF), a traditional herbal prescription, has been used clinically for AE-IPF, but its molecular mechanisms remain unclear. This study aimed to elucidate the pharmacological mechanisms and active constituents of KHF. Methods A bleomycin-induced AE-IPF mouse model was established to evaluate the therapeutic effects of KHF using histopathology, immunofluorescence, and inflammatory assessments. Network pharmacology was applied to predict targets, followed by drug affinity responsive target stability (DARTS) to identify direct binding proteins. Quantitative proteomics was used to validate target-related protein expression and pathway changes in vivo . Liquid chromatography–tandem mass spectrometry (LC–MS/MS) and molecular docking were used for compound–target analysis, and mechanistic validation was performed in macrophages using the glucose transporter 1 (GLUT1, encoded by SLC2A1) inhibitor STF-31 and cellular thermal shift assay (CETSA). Results KHF markedly alleviated lung injury in AE-IPF mice, as shown by reduced collagen deposition, decreased levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and high mobility group box 1 (HMGB1), and suppression of abnormal proliferation of alveolar type II epithelial cells. Network pharmacology suggested involvement of glycolysis-related pathways, including PI3K–Akt and HIF-1α signaling. DARTS and proteomics consistently identified GLUT1 as a core target. KHF inhibited glycolytic reprogramming, reflected by reduced expression of GLUT1, HIF-1α, and hexokinase 2 (HK2), along with decreased lactate production. LC–MS/MS and molecular docking identified rutin as a key GLUT1-targeting compound, which was further confirmed by CETSA. In macrophages, rutin showed anti-inflammatory and anti-glycolytic effects, and co-treatment with STF-31 showed no additive effects, suggesting a GLUT1-dependent mechanism. Conclusion KHF exerts anti-inflammatory and anti-fibrotic effects in AE-IPF, partly by modulating GLUT1-mediated glycolysis and regulating the GLUT1/HIF-1α axis, with rutin as a key bioactive component. These findings support the clinical application of KHF and highlight GLUT1-centered metabolic pathways as potential therapeutic targets.
Zhu et al. (Fri,) studied this question.