LARP6 regulates the mRNA translation of fibrogenic genes in liver fibrosis

Metabolic syndrome and excessive alcohol consumption result in liver injury and fibrosis, which is characterized by increased collagen production by activated Hepatic Stellate Cells (HSCs). LARP6, an RNA-binding protein, was shown to facilitate collagen production. However, LARP6 expression and functionality as a regulator of fibrosis development in a disease relevant model remains elusive. By using snRNA-sequencing, we show that LARP6 is upregulated mainly in HSCs of liver fibrosis patients. Moreover, LARP6 knockdown in human HSCs suppresses fibrogenic gene expression. By integrating eCLIP analysis and ribosome profiling in HSCs, we show that LARP6 interacts with mature mRNAs comprising over 300 genes, including RNA structural elements within COL1A1, COL1A2, and COL3A1 to regulate mRNA expression and translation. Furthermore, LARP6 knockdown in HSC attenuates fibrosis development in human liver spheroids. Altogether, our results suggest that targeting LARP6 in human HSCs may provide new strategies for anti-fibrotic therapy. HighlightsO_LILARP6 is upregulated in liver fibrosis, mainly in HSCs. C_LIO_LILARP6 knockdown in human HSCs reduces liver fibrosis development. C_LIO_LIOf the hundreds of gene targets, LARP6 interacts most with collagen mRNAs. C_LIO_LILARP6 regulates mRNA translation via interaction with 5UTRs. C_LI