Targeting TLR4 and regulating the Keap1/Nrf2 pathway with andrographolide to suppress inflammation and ferroptosis in LPS-induced acute lung injury  

作　　者：LI Yichen HUANG Liting LI Jilang LI Siyuan LV Jianzhen ZHONG Guoyue GAO Ming YANG Shilin HAN Shan HAO Wenhui 

机构地区：[1]Life Sciences Institute,Guangxi Medical University,Nanning 530021,China [2]College of Pharmacy,Guangxi University of Chinese Medicine,Nanning 530000,China [3]National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal.Medicine,Jiangxi University of Traditional Chinese Medicine,Nanchang 330006,China [4]Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases,Department of Biochemistry and Molecular Biology,School of Basic Medical Sciences,Xinjiang Medical University,Urumqi 830017,China

出　　处：《Chinese Journal of Natural Medicines》2024年第10期914-928,共15页中国天然药物（英文版）

基　　金：supported by China-ASEAN International Innovative Center for Health Industry of Traditional Chinese Medicine(No.AD20297142);Guangxi Collaborative Innovation Center for Scientific Achievements Transformation and Applicationon Traditional Chinese Medicine(No.05020058)。

摘　　要：Acute lung injury(ALI)is a severe inflammatory condition with a high mortality rate,often precipitated by sepsis.The pathophysiology of ALI involves complex mechanisms,including inflammation,oxidative stress,and ferroptosis,a novel form of regulated cell death.This study explores the therapeutic potential of andrographolide(AG),a bioactive compound derived from Andrographis,in mitigating Lipopolysaccharide(LPS)-induced inflammation and ferroptosis.Our research employed in vitro experiments with RAW264.7 macrophage cells and in vivo studies using a murine model of LPS-induced ALI.The results indicate that AG significantly suppresses the production of pro-inflammatory cytokines and inhibits ferroptosis in LPS-stimulated RAW264.7 cells.In vivo,AG treatment markedly reduces lung edema,decreases inflammatory cell infiltration,and mitigates ferroptosis in lung tissues of LPS-induced ALI mice.These protective effects are mediated via the modulation of the Toll-like receptor 4(TLR4)/Kelch-like ECH-associated protein 1(Keap1)/Nuclear factor erythroid 2-related factor 2(Nrf2)signaling pathway.Molecular docking simulations identified the binding sites of AG on the TLR4 protein(Kd value:-33.5 kcal·mol^(-1)),and these interactions were further corroborated by Cellular Thermal Shift Assay(CETSA)and SPR assays.Collectively,our findings demonstrate that AG exerts potent anti-inflammatory and anti-ferroptosis effects in LPS-induced ALI by targeting TLR4 and modulating the Keap1/Nrf2 pathway.This study underscores AG's potential as a therapeutic agent for ALI and provides new insights into its underlying mechanisms of action.

关 键 词：ANDROGRAPHOLIDE Acute lung injury Ferroptosis Toll-like receptor 4 Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2-related factor 2 

分 类 号：R965[医药卫生—药理学]