The present data demonstrated the novel anticancer mechanism of the DRD2 antagonist, penfluridol, in human ccRCC which harbors the WT or mutant VHL. Penfluridol can trigger the ER stress-elicited GRP78/PERK/eIF2α/CHOP signaling pathway of the UPR, and suppress the Akt/GLI1/OCT4/Nanog axis which respectively led to autophagy and stemness inhibition and further induced apoptosis of ccRCC cells; the mechanism is schematically illustrated in Fig. 8. Here, EIF2AK3 is linked to nonpapillary renal cell carcinoma.