Erianin Induces Ferroptosis of Renal Cancer Stem Cells <i>via</i> Promoting <i>ALOX12</i>/<i>P53</i> mRNA N6-methyladenosine Modification

Abstract

Renal cell carcinoma (RCC) is the most common type of primary renal parenchymal malignancy in adults, with a high degree of malignancy and poor prognosis. Human renal cancer stem cells (HuRCSCs) are reported to be the main cause of drug resistance, metastasis, recurrence, and poor prognosis. Erianin is a low molecular-weight bibenzyl natural product extracted from <i>Dendrobium chrysotoxum</i>, which inhibits the <i>in vitro</i> and <i>in vivo</i> activity of a variety of cancer cells. However, the molecular mechanisms of Erianin's therapeutic effect on HuRCSCs are unknown. Here, we isolated CD44+/CD105+ HuRCSCs from patients with renal cell carcinoma. The experiments confirmed that Erianin significantly inhibited the proliferation, invasion, angiogenesis, and tumorigenesis of HuRCSCs, and induced oxidative stress injury and Fe²⁺ accumulation. qRT-PCR and western blotting showed that Erianin significantly reduced the expression levels of cellular Ferroptosis protective factors, and upregulated the expression of METTL3 and downregulated that of FTO. Dot blotting results indicated that Erianin significantly upregulated the mRNA N6-methyladenosine (m6A) modification of HuRCSCs. The results of RNA immunoprecipitation-PCR also indicated that Erianin significantly enhanced the m6A modification level of the 3' untranslated region of <i>ALOX12</i> and <i>P53</i> mRNA in HuRCSCs, resulting in increased stability, prolonged half-life, and improved translation activity. In addition, clinical data analysis showed that the expression of <i>FTO</i> correlated negatively with adverse events in patient with renal cell carcinoma. Thus, this study suggested that Erianin can induce Ferroptosis in renal cancer stem cells by promoting N6-methyladenosine modification of <i>ALOX12</i>/<i>P53</i> mRNA, ultimately achieving a therapeutic effect on renal cancer.