[Mechanistic study on micheliolide alleviating pulmonary fibrosis by remodeling macrophage mitochondrial metabolism and dynamics via targeting PTGS-2 and GSK3β].

Authors

Chen Cui, Wanxue Wang, Hanqing Xu, Xiaohui Guo, Kegong Chen

Published in

Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology. Volume 42. Issue 11. Pages 992-1003.

Abstract

Objective To evaluate the therapeutic effects of compound micheliolide (MCL) against bleomycin (BLM)-induced pulmonary fibrosis (PF) and elucidate its underlying mechanisms. Methods A mouse model of BLM-induced PF was established. The effects of MCL on lung inflammation, mitochondrial damage, collagen deposition, and fibrosis-related protein expression were assessed using bronchoalveolar lavage fluid cell counting, total protein detection, lung tissue hydroxyproline content measurement, HE and Masson staining, and Western blot analysis. Macrophages were cultured in vitro, and CCK-8 assay, immunofluorescence, ELISA, and qRT-PCR were employed to evaluate the effects of MCL on cell viability, phenotypic polarization, and inflammatory cytokine secretion under BLM stimulation. Network pharmacology was used to screen potential targets and pathways, followed by molecular docking and Western blot validation to confirm the binding of MCL with key targets. Furthermore, reactive oxygen species (ROS) levels, mitochondrial dynamics-related proteins, and cellular oxygen consumption rate (OCR) were measured to evaluate the effects of MCL on mitochondrial function in macrophages. Results In vivo, MCL treatment significantly alleviated BLM-induced pulmonary inflammatory infiltration, mitochondrial ultrastructural damage and collagen deposition, and reduced the expression of fibrosis-related proteins α-smooth muscle actin (α-SMA) and collagen I (Col I). In vitro, MCL inhibited macrophage polarization toward the M2 phenotype, as evidenced by downregulating arginase 1 (Arg1) and mannose receptor 1 (CD206); moreover, it reduced the secretion of the pro-fibrotic factor transforming growth factor β1 (TGF-β1), and increased the release of the anti-inflammatory cytokine interleukin 10 (IL-10). Network pharmacology predicted prostaglandin-endoperoxide synthase 2 (PTGS-2) and glycogen synthase kinase-3 beta (GSK3β) as potential nodes action targets of MCL; molecular docking demonstrated a strong affinity between MCL and both targets, and Western blot analysis confirmed that MCL synergistically downregulated their expression. Additionally, MCL reduced intracellular ROS accumulation, modulated mitochondrial dynamics by downregulating dynamin-related protein 1 (DRP1) and upregulating mitofusin 2 (MFN2), and restored impaired mitochondrial respiratory function as indicated by increased OCR. Conclusion MCL may alleviate BLM-induced pulmonary fibrosis by targeting the PTGS-2 and GSK3β signaling pathways, thereby inhibiting macrophage M2 polarization and improving mitochondrial dynamics and metabolic function.

PMID:
43009328
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.