Previous studies have identified that lens epithelium-derived growth factor (LEDGF) interacts with SETD2-dependent histone H3 trimethylated at lysine 36 (H3K36me3) to mediate transcriptional elongation. However, the original LEDGF recognition H3K36me3 epigenetic regulatory axis no longer exists in SETD2 mutant clear cell renal cell carcinoma (ccRCC) patients, and a new transcription system needs to be discovered. In this study, the authors demonstrated the novel interaction between LEDGF and H3R17me2a. In detail, Asn38 and Asp57 of LEDGF Proline-Tryptophan-Tryptophan-Proline (PWWP) domain are the key binding sites validated by peptide pull-down assays. Subsequently, a series of in vitro and in vivo experiments showed that PPAT, PAICS, GART, ADSL, and ADSS2 are key target genes. Collectively, LEDGF binds H3R17me2a to regulate purine nucleotide metabolism in SETD2 mutant ccRCC cells, promoting tumor proliferation, and may be an effective therapeutic target.