Renal cell carcinoma(RCC)is the most common epithelial malignancy of the kidney in adults and accounts for approximately 3%of adult malignancies and represents 90-95%of renal neoplasms in western countries.Until today,there is no reliable diagnostic and prognostic biomarker for ccRCC,though a constant effort has been made in the searching of candidates of ccRCC biomarkers.Tid1 is a human homolog of Drosophila tumor suppressor Tid56 and a member of the DnaJ co-chaperone family,which was classified to be a tumor suppressor,participating in multiple intracellular signaling pathways to regulate cell growth,cell survival and cell death.Tid1 has two alternatively spliced isoforms,Tid1-Land Tid1-S,which differ only at their carboxyl-terminal tails and have significantly different rates of protein import into mitochondria and half-lives in the cytosol.Here,we reported that the level of hTid1-S was significantly down-regulated in ccRCC tumor tissues compared to adjacent non-cancerous tissues and Kaplan-Meier survival analysis showed patients within low hTid1-S have much poor outcomes.Furthermore,Cox`proportional hazards model showed that hTid1-S could be considered as a independent prognostic factor of ccRCC.To validate the role of hTid1in regulate cancer growth,we overexpressed hTid1-S in 786-0 and OS-RC-2 cancer cells.And cell proliferation rate was dramatically reduced due to hTid1-S overexpression.Additionally,cellular ROS level was increased while mitochondrial membrane potential was significantly decreased in hTid1-S overexpressed cancer cells which indicated that the tumor suppressor properties of hTid1-S.We found that exogenous hTid1-S overexpression activates AMPK signaling which further suppress mTOR signaling transduction.Moreover,we detected the change of three vital molecules of MAPK signaling and found phosphorylation of p38,ERK,JNK were also remarkably decreased which supported the tumor suppressor activity of hTid1-S.And we also found increased OXPHOS activity due to hTid1-S ablation which suggested that hTid1-S may switch cellular metabolism from glycolysis to mitochondrial oxidative respiration.Together,our study revealed that hTid1-S may be a crucial candidate biomarker and/or target for the diagnosis and therapy of ccRCC.