{"doi":"10.1111/liv.15682","title":"<scp>miR</scp>‐21‐5p promotes <scp>NASH</scp>‐related hepatocarcinogenesis","abstract":"BACKGROUND AND AIMS: The mechanisms governing the progression of non-alcoholic fatty liver disease (NAFLD) towards steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remain elusive. Here, we evaluated the role of hsa-miRNA-21-5p in NASH-related hepatocarcinogenesis. METHODS: Hepatic hsa-miR-21-5p expression was evaluated in two cohorts of patients with biopsy-proven NAFLD (n = 199) or HCC (n = 366 HCC and n = 11 NAFLD-HCC). Serum/liver metabolomic profiles were correlated with hsa-miR-21-5p in NAFLD obese patients. Wild-type (WT) and Mir21 KO mice were fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks to induce NASH and NASH-HCC, respectively. RESULTS: In obese individuals, hsa-miR-21-5p expression increased with NAFLD severity and associated with a hepatic lipotoxic profile. CDAA-fed WT mice displayed increased hepatic mmu-miR-21-5p levels and progressively developed NASH and fibrosis, with livers presenting macroscopically discernible pre-neoplastic nodules, hyperplastic foci and deregulated cancer-related pathways. Mir21 KO mice exhibited peroxisome-proliferator-activated receptor α (PPARα) activation, augmented mitochondrial activity, reduced liver injury and NAS below the threshold for NASH diagnosis, with the pro-inflammatory/fibrogenic milieu reversing to baseline levels. In parallel, Mir21 KO mice displayed reduced number of pre-neoplastic nodules, hepatocyte proliferation and activation of oncogenic signalling, being protected from NASH-associated carcinogenesis. The hsa-miRNA-21-5p/PPARα pathway was similarly deregulated in patients with HCC- or NASH-related HCC, correlating with HCC markers and worse prognosis. CONCLUSIONS: Hsa-miR-21-5p is a key inducer of whole-spectrum NAFLD progression, from simple steatosis to NASH and NASH-associated carcinogenesis. The inhibition of hsa-miR-21-5p, leading to a pro-metabolic profile, might constitute an appealing therapeutic approach to ameliorate NASH and prevent progression towards HCC.","journal":"Liver International","year":2023,"id":320632,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":48,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8935,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1031809,"name":"Marta B. Afonso","orcid":"0000-0003-3011-4941","position":1,"is_corresponding":false},{"id":1031810,"name":"André L. Simão","orcid":"0000-0002-5986-1089","position":2,"is_corresponding":false},{"id":1031811,"name":"Tawhidul Islam","orcid":"0000-0002-2513-1088","position":3,"is_corresponding":false},{"id":677965,"name":"Maria Manuela Gaspar","orcid":"0000-0001-6814-7226","position":4,"is_corresponding":false},{"id":291436,"name":"Colm J. O’Rourke","orcid":"0000-0002-2224-2663","position":5,"is_corresponding":false},{"id":894760,"name":"Monika Lewińska","orcid":"0000-0002-5275-992X","position":6,"is_corresponding":false},{"id":291447,"name":"Jesper B. Andersen","orcid":"0000-0003-1760-5244","position":7,"is_corresponding":false},{"id":859011,"name":"Enara Arretxe","orcid":"0000-0001-6413-6132","position":8,"is_corresponding":false},{"id":260304,"name":"Cristina Alonso","orcid":"0000-0002-2019-678X","position":9,"is_corresponding":false},{"id":1031812,"name":"Álvaro Santos‐Laso","orcid":"0000-0001-9810-4913","position":10,"is_corresponding":false},{"id":859013,"name":"Laura Izquierdo‐Sánchez","orcid":"0000-0002-7016-8314","position":11,"is_corresponding":false},{"id":1031813,"name":"Raúl Jiménez-Agüero","orcid":"0000-0002-5142-8491","position":12,"is_corresponding":false},{"id":1032575,"name":"Emma Eizaguirre","orcid":null,"position":13,"is_corresponding":false},{"id":94954,"name":"Luís Bujanda","orcid":"0000-0002-4353-9968","position":14,"is_corresponding":false},{"id":1032576,"name":"María Jesús Pareja","orcid":null,"position":15,"is_corresponding":false},{"id":1031814,"name":"Carina Prip‐Buus","orcid":"0000-0002-2153-7857","position":16,"is_corresponding":false},{"id":262974,"name":"Jesús M. Bañales","orcid":"0000-0002-5224-2373","position":17,"is_corresponding":false},{"id":243084,"name":"Cecília M. P. Rodrigues","orcid":"0000-0002-4829-754X","position":18,"is_corresponding":false},{"id":1031815,"name":"Rui E. Castro","orcid":"0000-0002-7417-0091","position":19,"is_corresponding":false},{"id":657327,"name":"Pedro M. Rodrigues","orcid":"0000-0001-6193-7436","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T01:07:27.434133Z","pmid":"37534739","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}