铜引起的新型细胞死亡方式——铜金属诱导的细胞死亡（cuproptosis）参与多种化疗药物的抗肿瘤活性和耐药性。我们先前的研究发现肾透明细胞癌（ccRCC）中肾上腺髓质素（ADM）参与舒尼替尼耐药性。然而，目前尚未调查ADM是否以及如何通过cuproptosis调控舒尼替尼的耐药性。本研究发现舒尼替尼耐药ccRCC组织和细胞中ADM表达升高。此外，ADM的上调显著增强了舒尼替尼的化疗耐药性，与各自对照相比。此外，cuproptosis参与ADM调控的舒尼替尼耐药性，通过抑制哺乳动物类铁硫蛋白1（FDX1）的表达。机械上，ADM的上调激活p38/MAPK信号通路，促进Forkhead box O3（FOXO3）的磷酸化和进入细胞核。因此，细胞核中FOXO3的增加抑制了FDX1的转录和细胞cuproptosis，促进了化疗耐药性。总之，cuproptosis在ccRCC进展和化疗耐药性中发挥关键作用，因此是根除舒尼替尼耐药细胞群体的相关靶标。© 2023美国实验生物学会。

Cuproptosis, a new type of copper-induced cell death, is involved in the antitumor activity and resistance of multiple chemotherapeutic drugs. Our previous study revealed that adrenomedullin (ADM) was engaged in sunitinib resistance in clear cell renal cell carcinoma (ccRCC). However, it has yet to be investigated whether and how ADM regulates sunitinib resistance by cuproptosis. This study found that the ADM expression was elevated in sunitinib-resistant ccRCC tissues and cells. Furthermore, the upregulation of ADM significantly enhanced the chemoresistance of sunitinib compared with their respective control. Moreover, cuproptosis was involved in ADM-regulated sunitinib resistance by inhibiting mammalian ferredoxin 1 (FDX1) expression. Mechanically, the upregulated ADM activates the p38/MAPK signaling pathway to promote Forkhead box O3 (FOXO3) phosphorylation and its entry into the nucleus. Consequently, the increased FOXO3 in the nucleus inhibited FDX1 transcription and cell cuproptosis, promoting chemoresistance. Collectively, cuproptosis has a critical effector role in ccRCC progress and chemoresistance and thus is a relevant target to eradicate the cell population of sunitinib resistance.© 2023 Federation of American Societies for Experimental Biology.