文献类型：期刊文献

英文题名：Qingfei Tongluo Formula attenuates COPD-associated ferroptosis by restoring arachidonic acid metabolic balance via dual inhibition of prostaglandin-endoperoxide synthase 2 and soluble epoxide hydrolase 2

作者：Wang, Yanru[1,2,3];Tian, Yawen[4];Bai, Jiaxu[1];Zhao, Jiali[1];Sun, Hailong[1];Hu, Guang[5];Yao, Juan[4];Liu, Xuefeng[4];Zhang, Zhiming[1,6];Jin, Xiaojie[1,4];Liu, Yongqi[1,2,3]

第一作者：王云荣;Wang, Yanru

通信作者：Zhang, ZM[1];Jin, XJ[1];Liu, YQ[1]

机构：[1]Gansu Univ Chinese Med, Key Lab Dunhuang Med, Minist Educ, Lanzhou 730000, Peoples R China;[2]Gansu Univ Chinese Med, Gansu Univ Key Lab Mol Med & Chinese Med Prevent &, Lanzhou 730000, Peoples R China;[3]Gansu Basic Disciplines Res Ctr Dunhuang Med, Lanzhou 730000, Peoples R China;[4]Gansu Univ Chinese Med, Coll Pharm, Lanzhou 730000, Peoples R China;[5]Soochow Univ, Ctr Syst Biol, Sch Biol & Basic Med Sci, Dept Bioinformat, Suzhou 215000, Peoples R China;[6]Gansu Prov Hosp Tradit Chinese Med, Lanzhou 730000, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Key Lab Dunhuang Med, Minist Educ, Lanzhou 730000, Peoples R China.|[10735]甘肃中医药大学;

年份：2026

卷号：157

外文期刊名：PHYTOMEDICINE

收录：;Scopus(收录号：2-s2.0-105039835055);WOS:【SCI-EXPANDED(收录号:WOS:001781333900001)】；

基金：This study was financially supported by the Outstanding Leading Talents Project of Gansu Province (Grant No. GSBJ-2024-12) , Regional Joint Innovation Key Project of the National Natural Science Foundation of China (Grant No. U23A20502) , and Major Science and Technology Project of Gansu Province (Grant No. 22ZD1FA001) .

语种：英文

外文关键词：Traditional Chinese medicine (TCM); Chronic obstructive pulmonary disease (COPD); Arachidonic acid metabolism; PTGS2/EPHX2; Ferroptosis; Inflammation

摘要：Background: Chronic Obstructive Pulmonary Disease (COPD) remains a major global health challenge due to the lack of therapies that modify its disease progression. Qingfei Tongluo Formula (QFTLF), a classic TCM formula, has shown efficacy in COPD. However, its specific molecular mechanisms and active compounds remain undefined. Purpose: This study aimed to decipher the multi-target mechanism of QFTLF against COPD, and to systematically identify its key bioactive serum compounds. Methods: Based on pharmacodynamic evaluation in a COPD rat model and UPLC-MS/MS-based identification of QFTLF prototype serum compounds, we performed integrative multi-modal analysis, combining transcriptomics, proteomics, PS-V2N-based complex network, and single-cell RNA sequencing, to identify core targets, pathways and cell types regulated by prototype serum compounds. Key findings were further validated through in vivo and in vitro experiments. To identify key bioactive serum compounds, we employed a computer-aided drug design (CADD) pipeline, including induced fit docking, molecular dynamics simulations, and binding free energy calculations, with subsequent experimental confirmation via surface plasmon resonance (SPR). Results: Pharmacodynamic evaluation demonstrated that QFTLF significantly improved pulmonary function, lung histopathology and systemic inflammation in COPD rats, with efficacy comparable to the classic therapy aminophylline. UPLC-MS/MS analysis identified 58 prototype serum compounds. Multi-modal analysis and verification revealed that QFTLF downregulates prostaglandin-endoperoxide synthase 2 (PTGS2) and soluble epoxide hydrolase 2(EPHX2) while upregulating CYP2J2 in both COPD rat lung tissues and CSE-induced MLE-12 cells. This regulation restored arachidonic acid metabolic balance, increasing the anti-inflammatory and anti-oxidation metabolite 11,12-EET and decreasing the pro-inflammatory and pro-oxidation metabolite 11,12-DHET. Thereby, QFTLF suppressed downstream pathogenic indicators, including pro-inflammatory cytokine levels (TNF-alpha, IL-1 beta, IL-6), lipid peroxidation indicators (reduced GSH and T-SOD, and elevated MDA), and ferroptosis indicators (Fe2+accumulation, HMGB1 release, and GPX4 downregulation). This effect is mediated through inhibition of the PTGS2-PPAR gamma-CYP2J2 and the EPHX2 mediated pathway. Notably, the protective profiles of specific PTGS2 and EPHX2 inhibitors in CSE-induced MLE-12 cells closely paralleled those of QFTLF, providing further support for the involvement of these targets. Furthermore, CADD and SPR identified and validated 7 key serum compounds with high binding affinity: 4 for PTGS2 (Mudanpioside C, Baicalin, Vitexin, Aloe-emodin-8-O-(3-D-glucopyranoside) and 5 for EPHX2 (Hamamelitannin, Choerospondin, Vitexin, Nepitrin, Aloe-emodin-8-O-(3-D-glucopyranoside). Conclusion: Our results identify QFTLF as a novel naturally occurring dual inhibitor of PTGS2/EPHX2, which attenuates COPD-associated ferroptosis in lung epithelial cells (the primary site of COPD injury) by restoring arachidonic acid metabolic balance, thereby addressing a critical unmet clinical need in COPD by positioning the QFTLF and its key compounds as promising disease modifying candidates.