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Jiaqi Li,1,2 Jing Zhao,2 Huan Wang,2 Xiaohan Li,2 Aixia Liu,2 Qin Qin,1,3 Boan Li1,2 1Basic Medicine College, Navy Military Medical University of Chinese PLA, Shanghai 200433, People's Republic of China; 2Center for Clinical Laboratory, The 302nd Hospital of Chinese PLA, Beijing 100039, People's Republic of China; 3Department of Laboratory Medicine, Changhai Hospital, Navy Military Medical University of Chinese PLA, Shanghai 200433, People's Republic of China Background: Pregnane X receptor (PXR), which is a member of the nuclear receptor protein family (nuclear receptor subfamily 1 group I member 2 [NR 1I2]), mediates the drug-resistance in the hepatocellular carcinoma (HCC) via enhancing the expression of drug-resistance-related genes which accelerate the clearance of antitumor drugs, eg, sorafenib. However, there are few reports on miRNA targeting PXR participating in the epigenetic regulation of PXR in HCC cells. Materials and methods: TargetScan 7.2, an online method, was used to predict the miRNAs potentially targeting PXR. The expression of PXR and PXR downstream genes was detected by quantitative real-time PCR (qPCR) and Western blot. The clearance of sorafenib in HCC cells was monitored by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS). The effects of miRNA on sorafenib's efficacy were examined by in vitro methods, eg, MTT, and in vivo methods, eg, subcutaneous or intrahepatic tumor model. Results: By virtual screening, we identified that miR-140-3p possibly targets PXR and then confirmed that the overexpression of miR-140-3p via lentiviral particles inhibited the expression of PXR in HCC cells. The downregulation of PXR's expression by miR-140-3p led to the reduction of PXR downstream genes' expression, which finally resulted in the decelerating clearance of sorafenib in HCC cells and enhanced the sensitivity of HCC cells to sorafenib. The effect of miR-140-3p could not modulate the expression of mutated PXR and the effect of miR-140-3p could also be inhibited by miR-140-3p's inhibitor. Moreover, miR-140-3p enhanced the antitumor effect of sorafenib in both the subcutaneous and intrahepatic HCC tumor models. Conclusion: Our study suggests that targeting PXR by miR-140-3p is a promising strategy for enhancing sorafenib's efficacy during HCC treatment. Keywords: hepatocellular carcinoma, microRNA, pregnenolone X receptor, sorafenib