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The AU‐rich binding factor 1 (AUF1) is one of the well known adenylate‐uridylate‐rich element (ARE)‐specific RNA‐binding proteins (ARE‐BPs) for which dysregulation has been reported in various human cancers. However, the involvement of AUF1 in the initiation and progression of hepatocellular carcinoma (HCC) is still elusive. In this study, we aimed at exploring the clinical significance, function, and mechanism of the abnormal expression of AUF1 in HCC. Using a bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Liver Cancer Institute (LCI) database, we identified that AUF1 was abnormally highly expressed in HCC tissues and that the high expression of AUF1 was correlated with poor prognosis in patients with HCC. We also confirmed the increased AUF1 expression and its prognostic value in our HBV‐related HCC cohorts. AUF1 overexpression in hepatoma cells promoted cell proliferation and increased the resistance of hepatoma cells toward doxorubicin, whereas knockdown of AUF1 exerted the opposite effects. Mechanistically, we demonstrated that AKR1B10 was a critical target of AUF1 and was essential for sustaining the AUF1‐induced proliferation and drug resistance of hepatoma cells. AUF1 increased AKR1B10 expression by binding to the 3′UTR region of  AKR1B10  mRNA and stabilizing  AKR1B10  mRNA. Additionally, we demonstrated that E2F1 enhanced AUF1 expression in HCC at the transcription level. Our study revealed a novel role of AUF1 in promoting the development and drug resistance of HCC via the post‐transcriptional regulation of AKR1B10 expression. The E2F1/AUF1/AKR1B10 axis can serve as a potential therapeutic target in HCC.

E2F1‐mediated AUF1 upregulation promotes HCC development and enhances drug resistance via stabilization of AKR1B10