Emerging evidence has demonstrated that long noncoding RNAs (lncRNAs) are promising targets or agents for the treatment of human cancers. Most liver-specific lncRNAs exhibit loss of expression and act as tumor suppressors in liver cancer. Modulating the expression of these liver-specific lncRNAs is a potential approach for lncRNA-based gene therapy for hepatocellular carcinoma (HCC). Here, we report that the expression of the liver-specific lncRNA FAM99B is significantly decreased in HCC tissues and that FAM99B suppresses HCC cell proliferation and metastasis both in vitro and in vivo. FAM99B promotes the nuclear export of DDX21 through XPO1, leading to further cleavage of DDX21 by caspase3/6 in the cytoplasm. FAM99B inhibits ribosome biogenesis by inhibiting ribosomal RNA (rRNA) processing and RPS29/RPL38 transcription, thereby reducing global protein synthesis through downregulation of DDX21 in HCC cells. Interestingly, the FAM99B