Academic Journal
Naringin affects VEGFC/TGF-β1 to mediate intercellular communication in MASH through coordinated Src and p38 MAPK pathways.
| Τίτλος: | Naringin affects VEGFC/TGF-β1 to mediate intercellular communication in MASH through coordinated Src and p38 MAPK pathways. |
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| Συγγραφείς: | Li J; The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, People's Republic of China., Nie A; The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, People's Republic of China; School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, People's Republic of China., Mao F; The Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing 210096, People's Republic of China., Chen Z; The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, People's Republic of China., Kang H; The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, People's Republic of China., Yao K; The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, People's Republic of China., Chen Z; The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, People's Republic of China. Electronic address: zhiych123@163.com., Hong W; The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, People's Republic of China; School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, People's Republic of China. Electronic address: hongweibio@pku.edu.cn. |
| Πηγή: | Biochemical pharmacology [Biochem Pharmacol] 2026 Sep; Vol. 251 (Pt 1), pp. 118009. Date of Electronic Publication: 2026 Apr 25. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Original Publication: Oxford, New York [etc.] Paragamon Press. |
| Ιατρικοί όροι (MeSH): | Transforming Growth Factor beta1*/metabolism , p38 Mitogen-Activated Protein Kinases*/metabolism , Flavanones*/pharmacology , Flavanones*/therapeutic use , Vascular Endothelial Growth Factor C*/metabolism , Vascular Endothelial Growth Factor C*/genetics , Fatty Liver*/metabolism , Fatty Liver*/drug therapy , src-Family Kinases*/metabolism , MAP Kinase Signaling System*/drug effects , MAP Kinase Signaling System*/physiology, Animals ; Mice ; Male ; Mice, Inbred C57BL |
| Περίληψη: | Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is driven by dysregulated intercellular communication. While our prior work identified hepatocyte-derived vascular endothelial growth factor C (VEGFC) as the key driver recruiting pro-fibrotic Ly6Chigh monocytes (defining the "Who") and by dictating their functional positioning (defining the "Where") in fibrotic foci, the intracellular signaling mechanism ("How") translating this recruitment into fibrogenic output remained unknown. This study elucidates this mechanism and its therapeutic targeting by naringin (NAR). In HFD-induced MASH mice and Vegfc△hep genetic models, both NAR and the vascular endothelial growth factor receptor-3 (VEGFR3) inhibitor SAR131675 attenuated hepatic steatosis, inflammation, and fibrosis, concomitant with reduced hepatic VEGFC expression and improved liver-to-body weight ratios. Mechanistically, VEGFC activation of macrophage VEGFR3 triggers Src/p38 MAPK signaling pathway, driving transforming growth factor-β (TGF-β1) production and inducing a pathological hybrid polarization-distinct from classical M1-type macrophages (M1)/ M2-type macrophages (M2) classification-characterized by concurrent nitric oxide synthase 2 (Nos2) and Tgf-β1 upregulation, Arginase 1 (Arg1) suppression, and unchanged macrophage mannose receptor 1 (Cd206) in both RAW264.7 cells and primary bone marrow-derived macrophages. This macrophage-derived TGF-β1 critically mediates hepatic stellate cells (HSCs) activation. These findings define the complete "Who/Where/How" pathogenic relay in MASH fibrosis and establish the VEGFC-VEGFR3-Src/p38 MAPK-TGF-β1 axis as the pharmacological target of NAR. (Copyright © 2026. Published by Elsevier Inc.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Intercellular communication; Liver fibrosis; MASH; Naringin; Src pathway; TGF-β1; VEGFC; p38 MAPK pathway |
| Substance Nomenclature: | 0 (Transforming Growth Factor beta1) EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) 0 (Flavanones) N7TD9J649B (naringin) 0 (Vascular Endothelial Growth Factor C) EC 2.7.10.2 (src-Family Kinases) |
| Entry Date(s): | Date Created: 20260427 Date Completed: 20260712 Latest Revision: 20260712 |
| Update Code: | 20260713 |
| DOI: | 10.1016/j.bcp.2026.118009 |
| PMID: | 42044813 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-2968 |
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| DOI: | 10.1016/j.bcp.2026.118009 |