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Here, we evaluated the role of hsa\u2010miRNA\u201021\u20105p in NASH\u2010related hepatocarcinogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Hepatic hsa\u2010miR\u201021\u20105p expression was evaluated in two cohorts of patients with biopsy\u2010proven NAFLD (<jats:italic>n<\/jats:italic>\u2009=\u2009199) or HCC (<jats:italic>n<\/jats:italic>\u2009=\u2009366 HCC and <jats:italic>n<\/jats:italic>\u2009=\u200911 NAFLD\u2010HCC). Serum\/liver metabolomic profiles were correlated with hsa\u2010miR\u201021\u20105p in NAFLD obese patients. Wild\u2010type (WT) and <jats:italic>Mir21<\/jats:italic> KO mice were fed a choline\u2010deficient, amino acid\u2010defined (CDAA) diet for 32 and 66\u2009weeks to induce NASH and NASH\u2010HCC, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In obese individuals, hsa\u2010miR\u201021\u20105p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA\u2010fed WT mice displayed increased hepatic mmu\u2010miR\u201021\u20105p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre\u2010neoplastic nodules, hyperplastic <jats:italic>foci<\/jats:italic> and deregulated cancer\u2010related pathways. <jats:italic>Mir21<\/jats:italic> KO mice exhibited peroxisome\u2010proliferator\u2010activated receptor \u03b1 (PPAR\u03b1) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro\u2010inflammatory\/fibrogenic milieu reversing to baseline levels. In parallel, <jats:italic>Mir21<\/jats:italic> KO mice displayed reduced number of pre\u2010neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH\u2010associated carcinogenesis. The hsa\u2010miRNA\u201021\u20105p\/PPAR\u03b1 pathway was similarly deregulated in patients with HCC\u2010 or NASH\u2010related HCC, correlating with HCC markers and worse prognosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Hsa\u2010miR\u201021\u20105p is a key inducer of whole\u2010spectrum NAFLD progression, from simple steatosis to NASH and NASH\u2010associated carcinogenesis. The inhibition of hsa\u2010miR\u201021\u20105p, leading to a pro\u2010metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15682","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T11:36:05Z","timestamp":1691062565000},"page":"2256-2274","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["<scp>miR<\/scp>\u201021\u20105p promotes <scp>NASH<\/scp>\u2010related hepatocarcinogenesis"],"prefix":"10.1111","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6193-7436","authenticated-orcid":false,"given":"Pedro M.","family":"Rodrigues","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy Universidade de Lisboa  Lisbon Portugal"},{"name":"Department of Liver and Gastrointestinal Diseases Biodonostia Health 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