Arresting idiopathic pulmonary fibrosis progression:EZY-1 targets mTORC2 to inhibit senescence-associated secretory phenotypeOA
EZY-1,a bioactive compound derived from the edible seaweed Eucheuma,was identified as a potent and selective mechanistic target of rapamycin complex 2(mTORC2)inhibitor.This agent showed significant anti-fibrotic efficacy in a bleomycin-induced pulmonary fibrosis model by targeting multiple pathological pathways.Treatment with EZY-1 significantly reduced extracellular matrix deposition,as confirmed by reduced collagen accumulation and suppressed expression of fibrosis-associated markers.EZY-1 attenuated cellular senescence by downregulating senescence indicators such as p53,p27,p21,p16,and the senescenceassociatedβ-galactosidase(SA-β-gal)activity,decreasing the secretion of senescence-associated secretory phenotype factors.EZY-1 also restored G1/S phase cell cycle progression by upregulating cyclin-dependent kinase 4(CDK4)and CDK2 levels.These molecular responses substantially suppress epithelialmesenchymal transition and fibroblast activation.Mechanistic studies revealed that the anti-fibrotic effect of EZY-1 is primarily mediated through suppression of the mTORC2/PI3K/Akt signaling cascade,modulating the mTORC2→Akt→p53/p21→CDK4/2 axis.In vitro analyses confirmed these effects on mTORC2 inhibition.These findings propose EZY-1 as a promising therapeutic candidate for treating idiopathic pulmonary fibrosis via its multi-target role against core fibrotic mechanisms.
Mingjin Tu;Huajun Yu;Lili Chen;Xiaoqin Huang;Liuyan He;Rongrong Chen;Xilian Tang;Jun Wu;Haitao Zhang
Guangdong Medical University,Zhanjiang 524002,China Department of Respiratory and Critical Care Medicine,Affiliated Hospital of Guangdong Medical University,Guangdong Medical University,Zhanjiang 524002,ChinaLaboratory Animal Centre,Guangdong Medical University,Zhanjiang 524002,ChinaGuangdong Medical University,Zhanjiang 524002,China Department of Respiratory and Critical Care Medicine,Affiliated Hospital of Guangdong Medical University,Guangdong Medical University,Zhanjiang 524002,ChinaDepartment of Biochemistry and Molecular Biology,Guangdong Medical University,Zhanjiang 524002,China Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University,Zhanjiang 524002,ChinaGuangdong Medical University,Zhanjiang 524002,China Department of Respiratory and Critical Care Medicine,Affiliated Hospital of Guangdong Medical University,Guangdong Medical University,Zhanjiang 524002,ChinaDepartment of Respiratory and Critical Care Medicine,Affiliated Hospital of Guangdong Medical University,Guangdong Medical University,Zhanjiang 524002,China Department of Biochemistry and Molecular Biology,Guangdong Medical University,Zhanjiang 524002,ChinaDepartment of Biochemistry and Molecular Biology,Guangdong Medical University,Zhanjiang 524002,China Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University,Zhanjiang 524002,ChinaDepartment of Respiratory and Critical Care Medicine,Affiliated Hospital of Guangdong Medical University,Guangdong Medical University,Zhanjiang 524002,ChinaDepartment of Biochemistry and Molecular Biology,Guangdong Medical University,Zhanjiang 524002,China Peptide and Protein Research and Application Key Laboratory of Guangdong Medical University,Zhanjiang 524002,China
医药卫生
Alveolar epithelial cellCellular senescenceEZY-1FibroblastPulmonary fibrosis
《Food Science and Human Wellness》 2026 (6)
P.2741-2758,18
supported by Guangdong Basic and Applied Basic Research Foundation(Grant No.2024A1515013157 and 2026A1515012840)Zhanjiang Science and Technology Plan Project Grant(2023A01003)。
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