{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T03:03:26Z","timestamp":1789614206977,"version":"build-2803163510"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471068 81603035 81870599"],"award-info":[{"award-number":["81471068 81603035 81870599"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2018T110986"],"award-info":[{"award-number":["2018T110986"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Background and Purpose:<\/jats:bold> Activation of hepatic stellate cells (HSC) is a central driver of liver fibrosis. 5-lipoxygenase (5-LO) is the key enzyme that catalyzes arachidonic acid into leukotrienes. In this study, we examined the role of 5-LO in HSC activation and liver fibrosis.<\/jats:p><jats:p><jats:bold>Main Methods:<\/jats:bold> Culture medium was collected from quiescent and activated HSC for target metabolomics analysis. Exogenous leukotrienes were added to culture medium to explore their effect in activating HSC. Genetic ablation of 5-LO in mice was used to study its role in liver fibrosis induced by CCl<jats:sub>4<\/jats:sub> and a methionine-choline-deficient (MCD) diet. Pharmacological inhibition of 5-LO in HSC was used to explore the effect of this enzyme in HSC activation and liver fibrosis.<\/jats:p><jats:p><jats:bold>Key Results:<\/jats:bold> The secretion of LTB<jats:sub>4<\/jats:sub> and LTC<jats:sub>4<\/jats:sub> was increased in activated vs. quiescent HSC. LTB<jats:sub>4<\/jats:sub> and LTC<jats:sub>4<\/jats:sub> contributed to HSC activation by activating the extracellular signal-regulated protein kinase pathway. The expression of 5-LO was increased in activated HSC and fibrotic livers of mice. Ablation of 5-LO in primary HSC inhibited both mRNA and protein expression of fibrotic genes. <jats:italic>In vivo<\/jats:italic>, ablation of 5-LO markedly ameliorated the CCl<jats:sub>4<\/jats:sub>- and MCD diet-induced liver fibrosis and liver injury. Pharmacological inhibition of 5-LO in HSC by targeted delivery of the 5-LO inhibitor zileuton suppressed HSC activation and improved CCl<jats:sub>4<\/jats:sub>- and MCD diet-induced hepatic fibrosis and liver injury. Finally, we found increased 5-LO expression in patients with non-alcoholic steatohepatitis and liver fibrosis.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> 5-LO may play a critical role in activating HSC; genetic ablation or pharmacological inhibition of 5-LO improved CCl<jats:sub>4<\/jats:sub>-and MCD diet-induced liver fibrosis.<\/jats:p>","DOI":"10.3389\/fphar.2021.628583","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T18:03:26Z","timestamp":1613844206000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Inhibition of 5-Lipoxygenase in Hepatic Stellate Cells Alleviates Liver Fibrosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Shiyun","family":"Pu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinhui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuping","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangying","family":"Kuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1111\/j.1476-5381.2011.01649_1.x","article-title":"Guide to receptors and channels (GRAC), 5th edition","volume":"164","author":"Alexander","year":"2011","journal-title":"Br. 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