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At present, there are no approved drugs for treating skeletal muscle atrophy. Arachidonate 5\u2010lipoxygenase (Alox5) is a drug target for a number of diseases. However, pharmacological targeting of Alox5, and its role in skeletal muscle atrophy, is unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The potential effects of gene knockdown and pharmacological targeting of Alox5 on skeletal muscle atrophy were investigated using cell\u2010based models, animal models and human skeletal muscle primary cells. Malotilate, a clinically safe drug developed for enhancing liver regeneration and Alox5 inhibitor, was investigated as a repurposing candidate. Mechanism(s) of action in skeletal muscle atrophy was assessed by measuring the expression level or activation status of key regulatory pathways and validated using gene knockdown and RNA sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Myotubes treated with the atrophy\u2010inducing glucocorticoid, dexamethasone, were protected from catabolic responses by treatment with malotilate (+41.29%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Similar anti\u2010atrophy effects were achieved by gene knockdown of Alox5 (+30.4%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Malotilate produced anti\u2010atrophy effects without affecting the myogenic differentiation programme. In an in vivo model of skeletal muscle atrophy, malotilate treatment preserved muscle force\/strength (grip strength: +35.72%, latency to fall: +553.1%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), increased mass and fibre cross\u2010sectional area (quadriceps: +23.72%, soleus: +33.3%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01) and down\u2010regulated atrogene expression (Atrogin\u20101: \u221261.58%, Murf\u20101: \u201066.06%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Similar, beneficial effects of malotilate treatment were observed in an ageing muscle model, which also showed the preservation of fast\u2010twitch fibres (Type 2a: +56.48%, Type 2b: +37.32%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.01). Leukotriene B4, a product of Alox5 activity with inflammatory and catabolic functions, was found to be elevated in skeletal muscle undergoing atrophy (quadriceps: +224.4%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001). Cellular transcriptome analysis showed that targeting Alox5 up\u2010regulated biological processes regulating organogenesis and increased the expression of insulin\u2010like growth factor\u20101, a key anti\u2010atrophy hormone (+226.5%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Interestingly, these effects were restricted to the atrophy condition and not observed in normal skeletal muscle cultures with Alox5 inhibition. Human myotubes were also protected from atrophy by pharmacological targeting of Alox5 (+23.68%, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results shed new light on novel drug targets and mechanisms underpinning skeletal muscle atrophy. Alox5 is a regulator and drug target for muscle atrophy, and malotilate is an attractive compound for repurposing studies to treat this disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13092","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T23:24:07Z","timestamp":1665530647000},"page":"3062-3077","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Inhibiting 5\u2010lipoxygenase prevents skeletal muscle atrophy by targeting organogenesis signalling and insulin\u2010like growth factor\u20101"],"prefix":"10.1002","volume":"13","author":[{"given":"Hyun\u2010Jun","family":"Kim","sequence":"first","affiliation":[{"name":"New Drug Targets Laboratory, School of Life Sciences Gwangju Institute of Science and Technology  Gwangju South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon\u2010Wook","family":"Kim","sequence":"additional","affiliation":[{"name":"New Drug Targets Laboratory, School of Life Sciences Gwangju Institute of Science and Technology  Gwangju South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang\u2010Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"New Drug Targets Laboratory, School of Life Sciences Gwangju Institute of Science and Technology  Gwangju South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da\u2010Woon","family":"Jung","sequence":"additional","affiliation":[{"name":"New Drug Targets Laboratory, School of Life Sciences Gwangju Institute of Science and Technology  Gwangju South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2555-3069","authenticated-orcid":false,"given":"Darren R.","family":"Williams","sequence":"additional","affiliation":[{"name":"New Drug Targets Laboratory, School of Life Sciences Gwangju Institute of Science and Technology  Gwangju South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,11]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-13-1435-3_1"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3557"},{"key":"e_1_2_9_4_1","first-page":"139","article-title":"Lipoxygenases, nonheme iron\u2010containing enzymes","volume":"6","author":"Veldink GA","year":"1984","journal-title":"Adv Inorg Biochem"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2019.06.040"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05346-5"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2013.10.002"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10050737"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10565-016-9333-1"},{"key":"e_1_2_9_10_1","first-page":"121","article-title":"Malotilate: The new hope for a clinically effective agent for the treatment of liver disease","volume":"22","author":"Ryle PR","year":"1987","journal-title":"Alcohol Alcohol"},{"key":"e_1_2_9_11_1","first-page":"95","article-title":"Morphological, immunohistochemical and ultrastructural changes in dimethylnitrosamine [correction of dimenthylnitrosamine] induced liver injury. 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