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ABSTRACTSunitinib is the most commonly used first-line therapy for the treatment of advanced renal cell carcinoma (RCC), but intrinsic and extrinsic resistance to targeted therapies dramatically compromise the benefit of clinical outcome. Dissecting the underlying mechanisms and discovering reliable predictive biomarkers are urgently needed in clinic. Here, we discovered miR-885-5p was notably decreased after sunitinib treatment and associated with poor disease progression in clear cell renal cell carcinoma (ccRCC). In vitroand in vivostudies identified miR-885-5p inhibition contributed to sunitinib resistance. Mechanistically, sunitinib treatment reduced GATA1 expression, which in turn reduced its binding to MIR885 promoter and resulted in miR-885-5p downregulation in transcriptional level. In addition, PLIN3 was confirmed to be directly targeted by miR-885-5p and its upregulation significantly increased lipid droplets formation to decrease sunitinib sensitivity. Therefore, GATA1/miR-885-5p/ PLIN3 pathway may serve as a potential therapeutic strategy and a biomarker for sunitinib treatment in ccRCC.