Background <p>Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer, representing about 70–80% of all renal cell carcinomas. Cuproptosis, a recently identified mode of cell death, has increasingly been linked to tumor initiation, progression, and drug resistance. Our study provides the first evidence that the histone acetyltransferase KAT2A regulates cuproptosis in ccRCC by modulating histone H3 lysine 27 (H3K27) acetylation.</p> Methods <p>Our study commenced by establishing, through in vitro and in vivo experiments including CCK8 assays, angiogenesis assays, and Western Blot analysis, that cabozantinib and cuproptosis inducers exhibit synergistic anticancer effects. Subsequently, whole-transcriptome sequencing identified DHRS2 as a key regulatory gene. A series of functional experiments, including colony formation assays, cell proliferation assays, EdU staining, mitochondrial membrane potential staining, and ROS detection, were then conducted to systematically validate the tumor-suppressive role of DHRS2 and its pro-cuproptosis activity.Further investigation, by analyzing co-expressed genes, led us to identify KAT2A as a downstream effector molecule. We employed RNA immunoprecipitation (RIP) and rescue experiments to confirm the interaction between DHRS2 and KAT2A. To elucidate the molecular mechanism, CHIP-seq (chromatin immunoprecipitation sequencing) revealed that H3K27 acetylation promotes the transcription of GLS, a negative regulator of cuproptosis. This finding was subsequently validated through CHIP-qPCR and luciferase reporter gene assays.</p> Results <p>Our study reveals that in ccRCC, the combined treatment of cabozantinib and cuproptosis inducers leads to a significant upregulation of DHRS2. Functional experiments demonstrate that DHRS2 exerts a tumor-suppressive effect on ccRCC cells, effectively inhibiting their proliferation and growth. Mechanistically, DHRS2 post-transcriptionally represses KAT2A. Downregulation of KAT2A results in reduced H3K27 acetylation, which, as identified by CHIP-seq, leads to decreased transcriptional activation of its downstream target, GLS. As GLS acts as a negative regulator of cuproptosis, its diminished expression ultimately increases cuproptosis, thereby synergistically suppressing tumor growth.</p> Conclusions <p>Our findings demonstrate that DHRS2 suppresses the transcription of KAT2A, leading to reduced H3K27 acetylation levels. This, in turn, diminishes the transcriptional activation of its downstream target, GLS, ultimately inhibiting tumor growth. These results suggest that the combination of cabozantinib and cuproptosis inducers holds promise as a novel therapeutic strategy for ccRCC.</p>