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The pathogenesis of AILD is not clear, and it poses a serious threat to human life and health for a long time. Several case reports and observational studies have shown that the Epstein-Barr virus (EBV) is directly associated with AILD.However, the causal nature of the intrinsic association remains uncertain.In this study, we investigated the potential association between Epstein-Barr virus and AILDs using a two-sample Mendelian randomization analysis and generalized summary-data-based MR (GSMR) by integrating a genome-wide association study (GWAS) of five antibodies against EBV with the latest GWAS summary statistics for AILDs derived from the FinnGen database. Using summary data-based Mendelian randomization (SMR), we identified AILD-associated candidate genes linked to EBV-related single nucleotide polymorphisms (SNPs). Subsequent transcriptomic and single-cell RNA sequencing analyses were performed to elucidate their functional roles in disease pathogenesis and their interactions with immune cell populations. We found that Epstein-Barr nuclear antigen 1 (EBNA-1) may be a protective factor in autoimmune hepatitis (AIH), while our reverse MR analysis similarly found that autoimmune hepatitis may decrease the levels of EBNA-1 antibodies. More importantly, we found a positive correlation between ZEBRA antibodies and primary biliary cholangitis (PBC). In addition, according to post-GWAS analysis, five genes showed significant causal relationships with AIH and four genes with PBC, of which AIF1-positive B cells may play an important role in AIH, and M1 macrophages may play an important role in PBC progression.Our findings suggest a complex role for EBV in AILD pathogenesis, potentially acting as a double-edged sword. This study represents the first lines of genetic evidence linking EBV and AILDs, opening new avenues for understanding the etiology and potential therapeutic targets in these chronic liver conditions.<\/jats:p>","DOI":"10.1186\/s13568-025-01975-6","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T13:29:21Z","timestamp":1761571761000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multi-omics profiling uncovers paradoxical Epstein-Barr virus involvement in autoimmune liver disease pathogenesis"],"prefix":"10.1186","volume":"15","author":[{"given":"Linyi","family":"Zheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cenap","family":"G\u00fcng\u00f6r","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heming","family":"Ge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"issue":"1","key":"1975_CR1","doi-asserted-by":"publisher","first-page":"195","DOI":"10.2353\/ajpath.2008.070845","volume":"173","author":"KR Baumforth","year":"2008","unstructured":"Baumforth KR, Birgersdotter A, Reynolds GM, Wei W, Kapatai G, Flavell JR, Kalk E, Piper K, Lee S, Machado L, Hadley K, Sundblad A, Sjoberg J, Bjorkholm M, Porwit AA, Yap LF, Teo S, Grundy RG, Young LS, Murray PG (2008) Expression of the Epstein-Barr virus-encoded Epstein-Barr virus nuclear antigen 1 in Hodgkin\u2019s lymphoma cells mediates up-regulation of CCL20 and the migration of regulatory T cells. 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Specifically, the UK Biobank approved the release of summary statistics related to the UK Biobank. The FinnGen Biobank GWAS, executed by the FinnGen team, was sanctioned by the FinnGen Steering Committee, with summary statistics available for public downloads on the official website. All these data are de-identified, freely downloadable, and accessible without restriction.Given that our research entailed no collection of fresh primary data and was conducted entirely online, we did not require any new ethical approval.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"156"}}