Fenofibrate potentiates the therapeutic efficacy of EZH2 inhibitors on melanoma via TRIM21‐ and OTUD4‐mediated EZH2 ubiquitination

Background and Purpose EZH2 (enhancer of zeste homologue 2) inhibitors are an emerging class of drugs that target epigenetic regulation. However, their efficacy in solid tumours has been limited, partly due to drug‐induced upregulation of fatty acid synthesis. Combining lipid metabolic modulation with EZH2 inhibition may offer a promising strategy to enhance antitumor activity. Experimental Approach We conducted a screen of clinically approved lipid‐lowering drugs to identify candidates that could enhance the efficacy of EZH2 inhibitors and found that fenofibrate significantly potentiated the antitumor effects of EZH2 inhibition. Mechanistic studies revealed that this synergistic effect was associated with the degradation of EZH2 protein. To uncover the underlying regulatory pathway, we performed mass spectrometry analysis, which identified the E3 ubiquitin ligase TRIM21 and the deubiquitinase OTUD4 as key mediators of fenofibrate‐induced EZH2 degradation. Key Results Fenofibrate significantly enhanced the antitumor effects of EZH2 inhibitors in melanoma, independent of its conventional lipid‐lowering function. TRIM21 and OTUD4 were identified as critical mediators of this synergistic effect. Fenofibrate disrupted the non‐canonical functions of EZH2 by promoting its destabilization, thereby exerting dual effects—inhibiting EZH2 enzymatic activity and accelerating its degradation. Combination therapy with fenofibrate and EZH2 inhibitors resulted in a potent synergistic suppression of tumour growth. Conclusions and Implications Our findings reveal a previously unrecognized role for fenofibrate in augmenting EZH2‐targeted therapy. This study provides a novel strategy to improve the efficacy of epigenetic therapies in cancer by combining EZH2 inhibitors with fenofibrate, offering potential clinical benefits for precision oncology.