Hypoxia was a prominent feature of hepatocellular carcinoma cells (HCC), contributing to therapeutic resistance towards a variety chemotherapeutic agents including Topoisomerase I inhibitor SN38, with mechanism not yet fully understood, thus remaining a major clinical challenge.Herein, we present evidences that the hypoxiainduced nuclear translocation and accumulation of Yesassociated protein (YAP) acts as a survival input to promote hypoxicresistance to SN38 in HCC.YAP induction by hypoxia was not mediated by HIF1 α, since the manipulation of HIF1 α either by CoGl2, exogenous expression nor siRNA of HIF1 α imposed any effect on the phosphorylation or total level of YAP.Instead, mevalonateHMGCoA reductase (HMGCR) pathway may modulate the YAP pathway under hypoxia.Combined YAP inhibition by either siRNA or HMGCR inhibitor statins with SN38 achieved improved anticancer activities in HCC cells.Moreover, the increased anticancer efficacy of statins combined with irinotecan (the prodrug of SN38) was further validated in a human HCC HepG2 xenograft model in nude mice.Taken together, our findings identify YAP as a novel mechanism of hypoxicresistance to SN38.These results unveil the combined suppression of YAP (for instance, statins) and SN38 as a potential promising strategy to enhance treatment response of HCC patients, particularly those with advanced stage suffering from hypoxic resistance.