{"doi":"10.1126/scitranslmed.add3949","title":"An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis","abstract":"Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies. To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model. In advanced fibrosis, we found that an autocrine HSC signaling circuit emerged that was composed of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions were supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, neurotrophic receptor tyrosine kinase 3-neurotrophin 3, inhibited human HSC activation in culture and reversed advanced murine NASH fibrosis. In summary, we uncovered a repertoire of antifibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a therapeutic paradigm in which stage-specific therapies could yield enhanced antifibrotic efficacy in patients with advanced hepatic fibrosis.","journal":"Science Translational Medicine","year":2023,"id":315427,"datarank":0.7667981682534817,"base_score":5.111987788356544,"endowment":5.111987788356544,"self_citation_contribution":0.7667981682534817,"citation_network_contribution":0.0,"self_endowment_contribution":0.7667981682534817,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":165,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"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":1016578,"name":"Kenneth Li","orcid":"0000-0002-0696-5474","position":1,"is_corresponding":false},{"id":1017464,"name":"Eliana Pickholz","orcid":null,"position":2,"is_corresponding":false},{"id":628691,"name":"Ross Dobie","orcid":"0000-0001-9516-315X","position":3,"is_corresponding":false},{"id":1016579,"name":"Kylie P. Matchett","orcid":"0000-0001-8710-7721","position":4,"is_corresponding":false},{"id":236642,"name":"Neil C. Henderson","orcid":"0000-0002-2273-4094","position":5,"is_corresponding":false},{"id":987332,"name":"Chris Carrico","orcid":"0000-0003-0939-9006","position":6,"is_corresponding":false},{"id":1016580,"name":"Ian Driver","orcid":"0000-0002-2674-5532","position":7,"is_corresponding":false},{"id":347294,"name":"Martin Borch Jensen","orcid":"0000-0002-8875-0345","position":8,"is_corresponding":false},{"id":1016581,"name":"Li Chen","orcid":"0000-0002-3458-1830","position":9,"is_corresponding":false},{"id":1016582,"name":"Mathieu Petitjean","orcid":"0000-0003-3468-7114","position":10,"is_corresponding":false},{"id":646261,"name":"Dipankar Bhattacharya","orcid":"0000-0002-4737-9818","position":11,"is_corresponding":false},{"id":89671,"name":"Maria Isabel Fiel","orcid":"0000-0002-7314-6313","position":12,"is_corresponding":false},{"id":246511,"name":"Xiao Liu","orcid":"0000-0002-7608-5819","position":13,"is_corresponding":false},{"id":226038,"name":"Tatiana Kisseleva","orcid":"0000-0001-9107-2306","position":14,"is_corresponding":false},{"id":251302,"name":"Uri S. Alon","orcid":"0000-0002-5338-8593","position":15,"is_corresponding":false},{"id":251297,"name":"Miri Adler","orcid":"0000-0003-4687-7572","position":16,"is_corresponding":false},{"id":66191,"name":"Ruslan Medzhitov","orcid":"0000-0002-7021-2012","position":17,"is_corresponding":false},{"id":89666,"name":"Scott L. Friedman","orcid":"0000-0003-1178-6195","position":18,"is_corresponding":false},{"id":228958,"name":"Shuang Wang","orcid":"0000-0001-5037-4316","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:06:25.560098Z","pmid":"36599008","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":[]}