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von Hippel–Lindau (VHL) is a tumor suppressor frequently inactivated in renal cell carcinoma (RCC), and its loss is associated with aberrant DNA methylation. Here we demonstrate that VHL-deficient RCC cells are highly vulnerable to DNA methyltransferase (DNMT) inhibitors. US Food and Drug Administration-approved DNMT inhibitors, such as decitabine and azacitidine, and investigational agents including RX-3117 and SGI-1027 selectively suppressed the growth of VHL-deficient RCC cells. Mechanistically, VHL loss leads to HIF-2α-dependent transcriptional upregulation of DNMT1, resulting in widespread CpG hypermethylation. Transcriptomic profiling and an RNA interference-based rescue screen identified KCNK3, a putative tumor suppressor, as a key mediator of DNMT inhibitor-induced synthetic lethality in VHL-deficient RCC. The KCNK3 promoter is hypermethylated and transcriptionally repressed in VHL-deficient RCC, where treatment with DNMT inhibitors reverses this methylation, restoring KCNK3 expression and resulting in cell growth inhibition. Silencing KCNK3 significantly attenuated the antitumor effects of DNMT inhibitors both in vitro and in vivo. Further mechanistic analysis showed that KCNK3 reactivation triggers TNF-α, MAPK and apoptotic signaling pathways, contributing to the observed synthetic lethality. Collectively, these findings establish DNMT inhibition as a synthetic lethal strategy in VHL-deficient RCC and highlight a potential therapeutic vulnerability for personalized treatment approaches.

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