Pre-B-cell leukemia transcription factor 1 contributes to liver fibrosis by enabling IL-7 signaling in HSC

BACKGROUND AND AIMS: Liver fibrosis, when dysregulated, contributes to irreversible loss of hepatic structure and function, heralding end-stage liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) represent the common progenitor to myofibroblasts that produce extracellular matrix proteins to mediate liver fibrosis. In the present study, we investigated the role of Pre-B-cell leukemia transcription factor 1 (PBX1) in this process. APPROACH AND RESULTS: PBX1 was screened out of mining through liver fibrosis-related single-cell RNA-seq data sets as the most prominently upregulated transcription factor during HSC activation. Ingenuity pathway analysis, coupled with reporter assay and chromatin immunoprecipitation assay, demonstrated that Notch3 mediated the elevation of PBX1 expression at the transcriptional level in HSCs. PBX1 knockdown attenuated HSC-myofibroblast transition in vitro and liver fibrosis in mice. Integrated transcriptomic analysis suggested that PBX1 contributed to HSC activation by activating a host of pro-fibrogenic molecules, including IL-7 receptor (IL7R/CD127). Consistently, exposure to recombinant IL-7 promoted HSC activation, whereas IL7R knockdown hampered HSC activation. Mechanistically, IL7R interacted with TGF-β receptors (I/II) to trigger a pro-fibrogenic signaling cascade. Importantly, blockade of the IL-7-IL7R signaling with neutralizing antibodies markedly ameliorated liver fibrosis in mice. Finally, a positive correlation between PBX1, IL7R, and HSC activation was identified in patients with cirrhosis. CONCLUSIONS: Our data uncover a previously unappreciated role for PBX1 in HSC activation and provide proof of concept for targeting IL-7 signaling in the intervention of liver fibrosis.