Clear cell renal cell carcinoma (ccRCC) is the most lethal subtype of renal cancer, and its treatment options remain limited. Therefore, there is an urgent need to discover therapeutic agents for ccRCC treatment. Here, we demonstrate that dimethyl fumarate (DMF), an approved medication for multiple sclerosis [1] and psoriasis, can inhibit the proliferation of ccRCC cells. Mechanistically, hepatocyte nuclear factor 1β (HNF1B), a transcription factor highly expressed in ccRCC, is succinated by DMF at cysteine residues, leading to its proteasomal degradation. Furthermore, HNF1B interacts with and stabilizes Yes-associated protein (YAP), thus DMF-mediated HNF1B degradation decreases YAP protein level and the expression of its target genes, resulting in the suppression of ccRCC cell proliferation. Importantly, oral administration of DMF sensitizes ccRCC to sunitinib treatment and enhances its efficacy in mice. In summary, we provide evidences supporting DMF as a potential drug for clinical treatment of ccRCC by targeting HNF1B and reveal a previously unrecognized role of HNF1B in regulating YAP in ccRCC.