lncARSR is upregulated in HCC, associated with large tumor size and advanced BCLC stage, and indicts poor prognosis. overexpression of lncARSR enhances doxorubicin resistance of HCC cells in vitro and in vivo.while knockdown of lncARSR increases sensitivity of HCC cells to doxorubicin in vitro and in vivo. lncARSR physically associates with PTEN mRNA, promotes PTEN mRNA degradation, decreases PTEN expression, and activates PI3K/Akt pathway. the effects of lncARSR overexpression on doxorubicin resistance could be reversed by PI3K/Akt pathway inhibitor, and lncARSR knockdown-induced doxorubicin sensitivity could be reversed by PTEN depletion. Taken together,upregulated lncARSR promotes doxorubicin resistance in HCC via modulating PTEN-PI3K/Akt pathway, and implied that lncARSR may serve as a promising prognostic biomarker and therapeutic target for HCC chemo-resistance.high expression of lncARSR indicates poorer recurrence-free and overall survival.