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Fei Gao,1,* Xiaolin Yu,2,* Rongqin Meng,2 Jisheng Wang,1 Lin Jia1 1Department of Oncology, Sichuan Mental Health Center, The Third Hospital of Mianyang, Mianyang, People’s Republic of China; 2Department of Oncology, AVIC 363 Hospital, Chengdu, People’s Republic of China *These authors contributed equally to this work Background: STARD13 has been revealed to suppress tumor progression. However, the roles in regulating the stemness of hepatocellular carcinoma (HCC) cells are unclear. Methods: Quantitative real-time PCR (qRT-PCR) was used to detect STARD13 expression in HCC tissues and normal adjacent tissues. Kaplan Meier (KM)-plotter analysis was performed to analyze the correlation between STARD13 expression and overall survival of HCC patients. Cell spheroid formation and ALDH1 activity analysis were carried out to detect the effects of STARD13 on the stemness of HCC cells. Furthermore, immunofluorescent, luciferase reporter, RhoA GTPase and F-actin visualization assays were performed to explore the mechanisms contributing to STARD13-mediated effects. Results: STARD13 expression was significantly downregulated in HCC tissues compared with normal adjacent tissues, and was positively correlated with the overall survival of HCC patients. Functionally, overexpression of STARD13 inhibited cells stemness and enhanced 5-FU sensitivity in HCC cells. Mechanistically, STRAD13 overexpression suppressed RhoGTPase signaling and thus inhibited transcriptional factor YAP translocation from nuclear to cytoplasm, leading to the downregulation of transcriptional activity of YAP. Notably, the inhibitory effects of STARD13 on HCC cells stemness and 5-FU sensitivity were rescued by RhoA or YAP-5SA overexpression. Conclusion: Our results indicate that STARD13 could enhances 5-FU sensitivity by suppressing cancer stemness in hepatocellular carcinoma cells via attenuating YAP transcriptional activity. Keywords: 5-FU, hepatocellular carcinoma, STARD13, stemness, YAP