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.

透明细胞肾细胞癌（ccRCC）是肾癌最常见的亚型，与不良预后相关。据报道，组蛋白 H3 赖氨酸 36 甲基转移酶 SET 结构域 2 (SETD2) 在 ccRCC 中低水平表达且频繁突变。铁死亡是一种不同于细胞凋亡和坏死的死亡形式，近年来在肾癌中有所报道。然而，SETD2与肾癌铁死亡之间的关系尚不清楚。在这里，我们证明 SETD2 在 ccRCC 中低水平表达，并且与不良预后相关。此外，我们发现SETD2的敲除增加了肿瘤细胞中的脂质过氧化和Fe ²⁺水平，从而增加了erastin（一种铁死亡诱导剂）的敏感性。从机制上来说，SETD2 催化的组蛋白 H3 赖氨酸 36 三甲基化 (H3K36me3) 与亚铁螯合酶 (FECH) 启动子相互作用，调节其转录和铁死亡相关信号通路。总之，本研究表明，表观遗传分子 SETD2 的敲低显着增加了铁死亡诱导剂的敏感性，从而促进肿瘤细胞死亡，从而表明 SETD2 可能是 ccRCC 的潜在治疗靶点。