Multiomics analyses reveal pathological mechanisms of HBV infection and integration in liver cancer

Abstract Hepatitis B virus (HBV) infection and integration are important for hepatocellular carcinoma (HCC) initiation and progression, while disease mechanisms are still largely elusive. Here, we combined bulk and single‐cell sequencing technologies to tackle the disease mechanisms of HBV‐related 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‐cell regulon analysis in HBV‐infected hepatocytes, which showed remarkable interactions between AR and the complement system that, together with the X‐linked ZXDB regulon that contains albumin ( ALB ), probably contribute to HCC male predominance. Complement system dysregulation caused by HBV infection was further confirmed by analyses of single‐cell copy numbers and cell–cell communications. Finally, HBV infection‐associated immune cells presented critical defects, including TXNIP in T cells, TYROBP in NK cells, and the X‐linked TIMP1 in monocytes. We further experimentally validated our findings in multiple independent patient cohorts. Collectively, our work shed light on the pathogenesis of HBV‐related HCC and other liver diseases that affect billions of people worldwide.