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Here, we combined bulk and single\u2010cell sequencing technologies to tackle the disease mechanisms of HBV\u2010related HCC. We observed high HBV mutation rate and diversity only in tumors without HBV integration. We identified human somatic risk loci for HBV integration (VIMs). Transcription factors (TFs) enriched in VIMs were involved in DNA repair and androgen receptor (AR) signaling. Aberration of AR signaling was further observed by single\u2010cell regulon analysis in HBV\u2010infected hepatocytes, which showed remarkable interactions between AR and the complement system that, together with the X\u2010linked ZXDB regulon that contains albumin (<jats:italic>ALB<\/jats:italic>), probably contribute to HCC male predominance. Complement system dysregulation caused by HBV infection was further confirmed by analyses of single\u2010cell copy numbers and cell\u2013cell communications. Finally, HBV infection\u2010associated immune cells presented critical defects, including <jats:italic>TXNIP<\/jats:italic> in T cells, <jats:italic>TYROBP<\/jats:italic> in NK cells, and the X\u2010linked <jats:italic>TIMP1<\/jats:italic> in monocytes. We further experimentally validated our findings in multiple independent patient cohorts. Collectively, our work shed light on the pathogenesis of HBV\u2010related HCC and other liver diseases that affect billions of people worldwide.<\/jats:p>","DOI":"10.1002\/jmv.28980","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T09:05:34Z","timestamp":1690794334000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multiomics analyses reveal pathological mechanisms of HBV infection and integration in liver cancer"],"prefix":"10.1002","volume":"95","author":[{"given":"Mengbiao","family":"Guo","sequence":"first","affiliation":[{"name":"Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Institute of Healthy Aging Research Sun Yat\u2010sen University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linghao","family":"Zhao","sequence":"additional","affiliation":[{"name":"Eastern Hepatobiliary Surgery Hospital 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