Background &Aims Liver regeneration is a series of physio-pathological phenomena resulting in quantitative recovery from the loss of liver mass to compensate for decreased hepatic volume and impaired function.Clinically, liver regeneration has important implications because many therapeutic strategies for the surgical treatment of liver diseases, such as removal of liver tumors and liver transplantation, depend on the ability of the liver to regenerate physically and functionally.Insufficient liver regeneration may be potentially fatal for these patients.Therefore, a better understanding of the mechanisms of liver regeneration could lead to clinical benefits.A complex network of cytokine and growth factor signaling involving molecules such as IL-6 and HGF regulates the hepatocyte cell cycle to ensure that liver regeneration occurs quickly.Recent studies have shown the critical role of miRNAs, such as miR-221 and miR-21, in liver regeneration.Although various cytokines, growth factors and miRNAs have been shown to regulate genes that orchestrate proliferation during liver regeneration, new molecular therapeutic targets for liver failure and liver transplantation are still urgently needed.It is important to understand the overall molecular changes that occur during liver regeneration to enhance the effectiveness of current regenerative technology.The mammalian genome encodes thousands of non-coding transcripts that have structural, regulatory or unknown functions.Although studies of small non-coding RNAs have dominated the field of RNA biology in recent years, long ncRNAs (lncRNAs)—defined as non-coding RNA molecules greater than 200 nucleotides in length—have been shown to play significant regulatory roles in X chromosomal inactivation, chromatin remodeling and transcriptional repression.LncRNAs also regulate multiple major biological processes, including development, differentiation and carcinogenesis.In our previous work, we showed that lncRNA-HEIH facilitates tumor cell growth through enhancer of zeste homolog 2.A recent study has implicated lncRNAs involved in liver regeneration.However, only preliminary studies have been conducted on the role of lncRNAs in liver regeneration, and the overall mechanisms remain largely unknown.Methods & Results: In this study, we carried out a genome-wide lncRNA microarray analysis during liver regeneration in mice after 2/3 partial hepatectomy (PH) at various time points.The results revealed differential expression of a subset of lncRNAs, notably a specific differentially expressed lncRNA associated with Wnt/β-Catenin signaling during liver regeneration (An LncRNA Associated with Liver Regeneration, termed lncRNA-LALR1).The functions of lncRNA-LALR1 were assessed by silencing and overexpressing this lncRNA in vitro and in vivo.We found that lncRNA-LALR1 enhanced hepatocyte proliferation by promoting progression of the cell cycle in vitro.Furthermore, we showed that lncRNA-LALR1 accelerated mouse hepatocyte proliferation and cell cycle progression during liver regeneration in vivo.Mechanistically, we discovered that lncRNA-LALR1 facilitated cyclin D1 expression through activation of Wnt/β-Catenin signaling via suppression of Axin1.In addition, lncRNA-LALR1 inhibited the expression of Axin1 mainly by recruiting CTCF to the AXTN1 promoter region.We also identified a human ortholog RNA of lncRNA-LALR1 (lncRNA-hLALR1) and found that it was expressed in human liver tissues.Conclusions: Our results indicate that lncRNA-LALR1 promotes cell cycle progression and accelerates hepatocyte proliferation during liver regeneration by activating Wnt/β-Catenin signaling.Thus, we propose that pharmacological intervention targeting lncRNA-LALR1 may be therapeutically beneficial in liver failure and liver transplantation by inducing liver regeneration.