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Furthermore, we identified suppressor of IKK\u03b5 (\n            <jats:italic>SIKE<\/jats:italic>\n            ) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of\n            <jats:italic>Sike<\/jats:italic>\n            prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-\u03b2\u2013activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated\n            <jats:italic>SIKE<\/jats:italic>\n            expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.ade7347","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T19:00:09Z","timestamp":1707937209000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8859-1540","authenticated-orcid":true,"given":"Lan","family":"Bai","sequence":"first","affiliation":[{"name":"Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China."},{"name":"State Key Laboratory of New Targets Discovery 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