清除细胞肾细胞癌（ccRCC）是最常见的肾癌亚型，与不良预后有关。组蛋白H3赖氨酸36甲基转移酶SET-结构域2（SETD2）已报道在ccRCC中表达水平低且频繁发生突变。近年来，在肾癌中报道了与细胞凋亡和坏死不同的死亡形式铁死亡。然而，SETD2与肾癌中铁死亡的关系尚不清楚。在这里，我们证明了SETD2在ccRCC中表达水平低且与不良预后有关。此外，我们发现SETD2的沉默增加了肿瘤细胞中脂质过氧化和Fe2+水平，从而增加了铁死亡诱导剂erastin的敏感性。从机制上讲，SETD2催化的组蛋白H3赖氨酸36三甲基化（H3K36me3）与铁螯合酶（FECH）的启动子相互作用，调控其转录和与铁死亡相关的信号通路。总之，本研究揭示了表观遗传分子SETD2的沉默显著增加了铁死亡诱导剂的敏感性，促进了肿瘤细胞死亡，因此表明SETD2可能是ccRCC的潜在治疗靶点。© 2023. 作者。

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is associated with poor prognosis. The histone H3 lysine 36 methyltransferase SET-domain-containing 2 (SETD2) has been reported to be expressed at low levels and frequently mutated in ccRCC. Ferroptosis, a form of death distinct from apoptosis and necrosis, has been reported in recent years in renal cancer. However, the relationship between SETD2 and ferroptosis in renal cancer is not clear. Here, we demonstrated that SETD2 was expressed at low levels in ccRCC and was associated with poor prognosis. Moreover, we found that knockdown of SETD2 increased lipid peroxidation and Fe2+ levels in tumor cells, thereby increasing the sensitivity of erastin, a ferroptosis inducer. Mechanistically, histone H3 lysine 36 trimethylation (H3K36me3) which was catalyzed by SETD2, interacted with the promoter of ferrochelatase (FECH) to regulate its transcription and ferroptosis-related signaling pathways. In conclusion, the presesnt study revealed that knockdown of the epigenetic molecule, SETD2, significantly increases the sensitivity of ferroptosis inducers which promotes tumor cell death, thereby indicating that SETD2 may be a potential therapeutic target for ccRCC.© 2023. The Author(s).