{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T16:11:48Z","timestamp":1779984708541,"version":"3.53.1"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Pharmacol Sin"],"published-print":{"date-parts":[[2022,8]]},"DOI":"10.1038\/s41401-021-00843-w","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T14:07:45Z","timestamp":1642514865000},"page":"2026-2041","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles"],"prefix":"10.1038","volume":"43","author":[{"given":"Ya-jing","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Run-ping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-ning","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-zhi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-yong","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-qing","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-ning","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-jie","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu-yong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojiaoyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"843_CR1","doi-asserted-by":"publisher","first-page":"7993","DOI":"10.7150\/thno.47826","volume":"10","author":"Y Li","year":"2020","unstructured":"Li Y, Liu R, Wu J, Li X. Self-eating: friend or foe? The emerging role of autophagy in fibrotic diseases. Theranostics. 2020;10:7993\u20138017.","journal-title":"Theranostics"},{"key":"843_CR2","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1002\/hep.28814","volume":"64","author":"P Hirsova","year":"2016","unstructured":"Hirsova P, Ibrahim SH, Verma VK, Morton LA, Shah VH, LaRusso NF, et al. Extracellular vesicles in liver pathobiology: small particles with big impact. Hepatology. 2016;64:2219\u201333.","journal-title":"Hepatology"},{"key":"843_CR3","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1002\/hep.30662","volume":"70","author":"R Liu","year":"2019","unstructured":"Liu R, Li X, Zhu W, Wang Y, Zhao D, Wang X, et al. Cholangiocyte-derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis. Hepatology. 2019;70:1317\u201335.","journal-title":"Hepatology"},{"key":"843_CR4","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1053\/j.gastro.2020.06.031","volume":"159","author":"D Dasgupta","year":"2020","unstructured":"Dasgupta D, Nakao Y, Mauer AS, Thompson JM, Sehrawat TS, Liao CY, et al. IRE1A stimulates hepatocyte-derived extracellular vesicles that promote inflammation in mice with steatohepatitis. Gastroenterology. 2020;159:1487\u2013503.e17.","journal-title":"Gastroenterology"},{"key":"843_CR5","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.jhep.2019.09.014","volume":"72","author":"F Jiang","year":"2020","unstructured":"Jiang F, Chen Q, Wang W, Ling Y, Yan Y, Xia P. Hepatocyte-derived extracellular vesicles promote endothelial inflammation and atherogenesis via microRNA-1. J Hepatol. 2020;72:156\u201366.","journal-title":"J Hepatol"},{"key":"843_CR6","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.jcmgh.2015.07.007","volume":"1","author":"D Povero","year":"2015","unstructured":"Povero D, Panera N, Eguchi A, Johnson CD, Papouchado BG, de Araujo Horcel L, et al. Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-\u03b3. Cell Mol Gastroenterol Hepatol. 2015;1:646\u201363.e4.","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"843_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16092-0","volume":"11","author":"P An","year":"2020","unstructured":"An P, Wei LL, Zhao S, Sverdlov DY, Vaid KA, Miyamoto M, et al. Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nat Commun. 2020;11:2362.","journal-title":"Nat Commun"},{"key":"843_CR8","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1007\/s12079-017-0421-7","volume":"12","author":"L Chen","year":"2018","unstructured":"Chen L, Chen R, Kemper S, Brigstock DR. Pathways of production and delivery of hepatocyte exosomes. J Cell Commun Signal. 2018;12:343\u201357.","journal-title":"J Cell Commun Signal"},{"key":"843_CR9","doi-asserted-by":"publisher","first-page":"368","DOI":"10.3389\/fcell.2019.00368","volume":"7","author":"X Li","year":"2019","unstructured":"Li X, Chen R, Kemper S, Brigstock DR. Extracellular vesicles from hepatocytes are therapeutic for toxin-mediated fibrosis and gene expression in the liver. Front Cell Dev Biol. 2019;7:368.","journal-title":"Front Cell Dev Biol"},{"key":"843_CR10","doi-asserted-by":"publisher","first-page":"e21680","DOI":"10.1096\/fj.202002678R","volume":"35","author":"H Dansako","year":"2021","unstructured":"Dansako H, Ueda Y, Satoh S, Kato N. Extracellular vesicles activate ATM-Chk2 signaling pathway through the intercellular transfer of mitochondrial DNA in HBV-infected human hepatocytes. FASEB J. 2021;35:e21680.","journal-title":"FASEB J"},{"key":"843_CR11","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1002\/iub.1598","volume":"69","author":"S Zhao","year":"2017","unstructured":"Zhao S, Zhang Z, Yao Z, Shao J, Chen A, Zhang F, et al. Tetramethylpyrazine attenuates sinusoidal angiogenesis via inhibition of hedgehog signaling in liver fibrosis. IUBMB Life. 2017;69:115\u201327.","journal-title":"IUBMB Life"},{"key":"843_CR12","doi-asserted-by":"publisher","first-page":"e12741","DOI":"10.1111\/acel.12741","volume":"17","author":"B Gao","year":"2018","unstructured":"Gao B, Lin X, Jing H, Fan J, Ji C, Jie Q, et al. Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti-inflammatory and angiogenic environment in aging mice. Aging Cell. 2018;17:e12741.","journal-title":"Aging Cell"},{"key":"843_CR13","doi-asserted-by":"publisher","first-page":"610","DOI":"10.7150\/thno.22237","volume":"8","author":"F Zhang","year":"2018","unstructured":"Zhang F, Lu S, He J, Jin H, Wang F, Wu L, et al. Ligand activation of PPAR\u03b3 by ligustrazine suppresses pericyte functions of hepatic stellate cells via SMRT-mediated transrepression of HIF-1\u03b1. Theranostics. 2018;8:610\u201326.","journal-title":"Theranostics"},{"key":"843_CR14","doi-asserted-by":"publisher","first-page":"153495","DOI":"10.1016\/j.phymed.2021.153495","volume":"84","author":"Y Cai","year":"2021","unstructured":"Cai Y, Xu B, Zhou F, Wu J, Li S, Zheng Q, et al. Si-Ni-San ameliorates chronic colitis by modulating type I interferons-mediated inflammation. Phytomedicine. 2021;84:153495.","journal-title":"Phytomedicine"},{"key":"843_CR15","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1002\/hep.29145","volume":"66","author":"X Li","year":"2017","unstructured":"Li X, Liu R, Yang J, Sun L, Zhang L, Jiang Z, et al. The role of long noncoding RNA H19 in gender disparity of cholestatic liver injury in multidrug resistance 2 gene knockout mice. Hepatology. 2017;66:869\u201384.","journal-title":"Hepatology"},{"key":"843_CR16","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.redox.2015.12.010","volume":"8","author":"RJ Mailloux","year":"2016","unstructured":"Mailloux RJ, Treberg JR. Protein S-glutathionlyation links energy metabolism to redox signaling in mitochondria. Redox Biol. 2016;8:110\u20138.","journal-title":"Redox Biol"},{"key":"843_CR17","doi-asserted-by":"crossref","unstructured":"Li X, Liu R, Wang Y, Zhu W, Zhao D, Wang X, et al. Cholangiocyte-derived exosomal lncRNA H19 promotes macrophage activation and hepatic inflammation under cholestatic conditions. Cells. 2020;9:190.","DOI":"10.3390\/cells9010190"},{"key":"843_CR18","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/s41580-019-0173-8","volume":"21","author":"FJ Bock","year":"2020","unstructured":"Bock FJ, Tait SWG. Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol. 2020;21:85\u2013100.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"843_CR19","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.jhep.2018.10.015","volume":"70","author":"M Ruart","year":"2019","unstructured":"Ruart M, Chavarria L, Campreci\u00f3s G, Su\u00e1rez-Herrera N, Montironi C, Guix\u00e9-Muntet S, et al. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J Hepatol. 2019;70:458\u201369.","journal-title":"J Hepatol"},{"key":"843_CR20","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/nature08780","volume":"464","author":"Q Zhang","year":"2010","unstructured":"Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464:104\u20137.","journal-title":"Nature"},{"key":"843_CR21","doi-asserted-by":"publisher","first-page":"37","DOI":"10.15252\/embj.201899238","volume":"37","author":"JS Riley","year":"2018","unstructured":"Riley JS, Quarato G, Cloix C, Lopez J, O'Prey J, Pearson M, et al. Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 2018;37:37.","journal-title":"EMBO J"},{"key":"843_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20303-z","volume":"12","author":"J Dong","year":"2021","unstructured":"Dong J, Viswanathan S, Adami E, Singh BK, Chothani SP, Ng B, et al. Hepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH. Nat Commun. 2021;12:66.","journal-title":"Nat Commun"},{"key":"843_CR23","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1007\/s12041-019-1072-7","volume":"98","author":"M Saikia","year":"2019","unstructured":"Saikia M, Nath R, Devi D. Genetic diversity and phylogeny analysis of Antheraea assamensis Helfer (Lepidoptera: Saturniidae) based on mitochondrial DNA sequences. J Genet. 2019;98:98.","journal-title":"J Genet"},{"key":"843_CR24","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1002\/hep.30928","volume":"71","author":"M Mooring","year":"2020","unstructured":"Mooring M, Fowl BH, Lum S, Liu Y, Yao K, Softic S, et al. Hepatocyte stress increases expression of yes-associated protein and transcriptional coactivator with PDZ-binding motif in hepatocytes to promote parenchymal inflammation and fibrosis. Hepatology. 2020;71:1813\u201330.","journal-title":"Hepatology"},{"key":"843_CR25","doi-asserted-by":"publisher","first-page":"2380","DOI":"10.1002\/hep.30093","volume":"68","author":"X Ge","year":"2018","unstructured":"Ge X, Arriazu E, Magdaleno F, Antoine DJ, Dela Cruz R, Theise N, et al. High mobility group box-1 drives fibrosis progression signaling via the receptor for advanced glycation end products in mice. Hepatology. 2018;68:2380\u2013404.","journal-title":"Hepatology"},{"key":"843_CR26","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.biopha.2016.01.018","volume":"78","author":"F Zhang","year":"2016","unstructured":"Zhang F, Jin H, Wu L, Shao J, Wu X, Lu Y, et al. Ligustrazine disrupts lipopolysaccharide-activated NLRP3 inflammasome pathway associated with inhibition of Toll-like receptor 4 in hepatocytes. Biomed Pharmacother. 2016;78:204\u20139.","journal-title":"Biomed Pharmacother"},{"key":"843_CR27","doi-asserted-by":"publisher","first-page":"9","DOI":"10.3390\/cells9040875","volume":"9","author":"N Roehlen","year":"2020","unstructured":"Roehlen N, Crouchet E, Baumert TF. Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells. 2020;9:9.","journal-title":"Cells"},{"key":"843_CR28","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.jhep.2017.10.015","volume":"68","author":"MA Konerman","year":"2018","unstructured":"Konerman MA, Jones JC, Harrison SA. Pharmacotherapy for NASH: current and emerging. J Hepatol. 2018;68:362\u201375.","journal-title":"J Hepatol"},{"key":"843_CR29","doi-asserted-by":"publisher","first-page":"2793","DOI":"10.1111\/bph.15007","volume":"177","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Jiang M, Cui BW, Jin CH, Wu YL, Shang Y, et al. P2X7 receptor-targeted regulation by tetrahydroxystilbene glucoside in alcoholic hepatosteatosis: a new strategy towards macrophage-hepatocyte crosstalk. Br J Pharmacol. 2020;177:2793\u2013811.","journal-title":"Br J Pharmacol"},{"key":"843_CR30","first-page":"603067","volume":"2015","author":"J Hu","year":"2015","unstructured":"Hu J, Cao G, Wu X, Cai H, Cai B. Tetramethylpyrazine inhibits activation of hepatic stellate cells through hedgehog signaling pathways in vitro. Biomed Res Int. 2015;2015:603067.","journal-title":"Biomed Res Int"},{"key":"843_CR31","doi-asserted-by":"publisher","first-page":"119331","DOI":"10.1016\/j.lfs.2021.119331","volume":"274","author":"X Ma","year":"2021","unstructured":"Ma X, Ruan Q, Ji X, Yang J, Peng H. Ligustrazine alleviates cyclophosphamide-induced hepatotoxicity via the inhibition of Txnip\/Trx\/NF-kappaB pathway. Life Sci. 2021;274:119331.","journal-title":"Life Sci"},{"key":"843_CR32","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1007\/112_2018_10","volume":"175","author":"T Luangmonkong","year":"2018","unstructured":"Luangmonkong T, Suriguga S, Mutsaers H, Groothuis G, Olinga P, Boersema M. Targeting oxidative stress for the treatment of liver fibrosis. Rev Physiol Biochem Pharmacol. 2018;175:71\u2013102.","journal-title":"Rev Physiol Biochem Pharmacol"},{"key":"843_CR33","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1007\/s00204-014-1302-y","volume":"89","author":"X Gong","year":"2015","unstructured":"Gong X, Ivanov VN, Davidson MM, Hei TK. Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death. Arch Toxicol. 2015;89:1057\u201370.","journal-title":"Arch Toxicol"},{"key":"843_CR34","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1126\/science.aav4011","volume":"366","author":"J Kim","year":"2019","unstructured":"Kim J, Gupta R, Blanco LP, Yang S, Shteinfer-Kuzmine A, Wang K, et al. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science. 2019;366:1531\u20136.","journal-title":"Science"},{"key":"843_CR35","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/j.jhep.2019.06.018","volume":"71","author":"W Seo","year":"2019","unstructured":"Seo W, Gao Y, He Y, Sun J, Xu H, Feng D, et al. ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles. J Hepatol. 2019;71:1000\u201311.","journal-title":"J Hepatol"},{"key":"843_CR36","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1172\/JCI83885","volume":"126","author":"I Garcia-Martinez","year":"2016","unstructured":"Garcia-Martinez I, Santoro N, Chen Y, Hoque R, Ouyang X, Caprio S, et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J Clin Invest. 2016;126:859\u201364.","journal-title":"J Clin Invest"},{"key":"843_CR37","doi-asserted-by":"publisher","first-page":"891","DOI":"10.3389\/fimmu.2018.00891","volume":"9","author":"A Aswani","year":"2018","unstructured":"Aswani A, Manson J, Itagaki K, Chiazza F, Collino M, Wupeng WL, et al. Scavenging circulating mitochondrial DNA as a potential therapeutic option for multiple organ dysfunction in trauma hemorrhage. Front Immunol. 2018;9:891.","journal-title":"Front Immunol"},{"key":"843_CR38","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.jnutbio.2019.06.001","volume":"71","author":"M Bae","year":"2019","unstructured":"Bae M, Lee Y, Park YK, Shin DG, Joshi P, Hong SH, et al. Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells. J Nutr Biochem. 2019;71:82\u201389.","journal-title":"J Nutr Biochem"},{"key":"843_CR39","first-page":"1255","volume":"12","author":"D Kong","year":"2020","unstructured":"Kong D, Chen L, Huang W, Zhang Z, Wang L, Zhang F, et al. Combined therapy with ligustrazine and paeonol mitigates hepatic fibrosis through destroying mitochondrial integrity of stellate cell. Am J Transl Res. 2020;12:1255\u201366.","journal-title":"Am J Transl Res"}],"container-title":["Acta Pharmacologica Sinica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00843-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00843-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00843-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T07:29:28Z","timestamp":1659338968000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00843-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":39,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["843"],"URL":"https:\/\/doi.org\/10.1038\/s41401-021-00843-w","relation":{},"ISSN":["1671-4083","1745-7254"],"issn-type":[{"value":"1671-4083","type":"print"},{"value":"1745-7254","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,13]]},"assertion":[{"value":"8 October 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}