{ "abstract": "Background: Since early 2022, a global surge in cases of severe acute hepatitis of unknown origin (AHUO) in children has been reported, with no definitive aetiology established. Epidemiological evidence suggests a potential link to SARS-CoV-2 infection, particularly during Omicron-predominant periods, yet the mechanisms underlying the apparently higher susceptibility of children to SARS-CoV-2-related liver injury remain poorly understood. This study used non-tumorous (tumor-adjacent) liver organoids derived from pediatric and adult donors to compare viral RNA accumulation and host immune responses to SARS-CoV-2 wild-type (WT) and Omicron (BA.1/BA.2) variants, aiming to explore the possible role of SARS-CoV-2 in pediatric acute hepatitis.\n\nMethods: Liver organoids were established from non-tumorous (tumor-adjacent) liver tissue of three adult patients with hepatocellular carcinoma and three pediatric patients with hepatoblastoma, collected between February and December 2022. Organoids were infected with SARS-CoV-2 WT, Omicron BA.1 or BA.2 at a multiplicity of infection (MOI) of 0.1. Viral loads in supernatants and intracellular viral RNA were quantified by RT-qPCR at 24 and 48 h post-infection (hpi). At 48 hpi, RNA-seq was performed to profile transcriptomic changes and pathway enrichment. Additionally, single-cell RNA-seq data were used to compare baseline expression of SARS-CoV-2 entry-associated genes between pediatric and adult hepatocytes.\n\nResults: Pediatric hepatocytes showed significantly higher basal expression of entry-related genes, including ASGR1, KREMEN1, CTSB, CTSL, and VIM, than adult cells. Both pediatric and adult liver organoids were permissive to WT and Omicron, but Omicron BA.1/BA.2 yielded higher intracellular viral RNA levels than WT, with notably higher intracellular viral RNA burden in pediatric organoids. RNA-seq revealed that Omicron infection induced a more pronounced innate-immune-associated transcriptional response in pediatric organoids—encompassing interferon signaling, RIG-I-like receptor and Toll-like receptor pathways—alongside relative downregulation of adaptive immune-pathway transcripts. In adult organoids, transcriptomic divergence between Omicron and WT was less pronounced. Compared with adults, Omicron-infected pediatric organoids upregulated interferon-γ signaling and other innate immune-associated transcriptional programs, while downregulating adaptive immune-pathway transcripts; key receptors such as ACE2 and TMPRSS4 remained consistently higher in pediatric organoids across all viral strains.\n\nConclusion: Pediatric liver organoids accumulate higher levels of Omicron viral RNA than WT-infected organoids and mount a stronger innate-immune transcriptional response alongside relative downregulation of adaptive immune-pathway transcripts, correlating with elevated expression of viral entry factors. These age-dependent in vitro differences raise the hypothesis that SARS-CoV-2, particularly Omicron, could contribute to hepatocyte injury in children; however, this organoid-based model does not include patients with acute hepatitis of unknown origin and cannot establish a causal or epidemiological link, which will require dedicated prospective clinical and mechanistic studies.", "abstract_shown": true, "affiliations": [ "Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University", "Department of Oncology, The First Affiliated Hospital, Sun Yat-sen University", "Guangdong Provincial Center for Disease Control and Prevention", "Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University" ], "article_type": "research article", "arxiv": null, "author_total": 10, "authors": [ { "affs": [ 0 ], "name": "Tianchen Xue" }, { "affs": [ 1 ], "name": "Jie Hu" }, { "affs": [ 2 ], "name": "Zhe Liu" }, { "affs": [ 3 ], "name": "Lefan Zhu" }, { "affs": [ 3 ], "name": "Yi Zhao" }, { "affs": [ 1 ], "name": "Xiaoxue Ren" }, { "affs": [ 1 ], "name": "Lixia Xu" }, { "affs": [ 3 ], "name": "Xiaoxing Li" }, { "affs": [ 2 ], "name": "Jing Lu" }, { "affs": [ 3 ], "name": "Lina Wang" } ], "bibtex": "https://research.draconitic.com/paper/6vpvxj1ywzptb.bib", "cited_by": 0, "doi": "10.3389/fpubh.2026.1951670", "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fpubh.2026.1951670/full", "id": "6vpvxj1ywzptb", "issns": [ "2296-2565" ], "landing_url": "https://www.frontiersin.org/articles/10.3389/fpubh.2026.1951670/full", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "lcc", "RA1-1270" ], [ "openalex", "2725|SARS-CoV-2 and COVID-19 Research" ] ], "openalex": "W7223284545", "pdf_url": "https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2026.1951670/pdf", "pmcid": "PMC13739785", "pmid": "42996705", "published": "2026-10-23", "publisher": "Frontiers Media SA", "ris": "https://research.draconitic.com/paper/6vpvxj1ywzptb.ris", "sources": [ { "first_seen": "2026-10-30T12:20:24Z", "native_id": "10.3389/fpubh.2026.1951670", "source": "crossref", "url": "https://www.frontiersin.org/articles/10.3389/fpubh.2026.1951670/full" }, { "first_seen": "2026-10-30T13:43:48Z", "native_id": "878ba8f7fd0d46589014e719e1a0af7f", "source": "doaj", "url": "https://doi.org/10.3389/fpubh.2026.1951670" }, { "first_seen": "2026-11-09T15:20:34Z", "native_id": "MED:42996705", "source": "europepmc", "url": "https://europepmc.org/article/MED/42996705" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2725|SARS-CoV-2 and COVID-19 Research", "subfield": "infectious-disease" } ], "title": "Age-dependent differences in SARS-CoV-2 entry-factor expression and innate immune responses between pediatric and adult liver organoids", "title_text": "Age-dependent differences in SARS-CoV-2 entry-factor expression and innate immune responses between pediatric and adult liver organoids", "type": "peer-reviewed", "updated_at": "2026-11-09T15:20:34Z", "url": "https://research.draconitic.com/paper/6vpvxj1ywzptb", "venue": "Frontiers in Public Health", "versions": [] }