Dual ferroptosis induction in N2-TANs and TNBC cells via FTH1 targeting: A therapeutic strategy for triple-negative breast cancer

作者：Yichen Liu, Qingyan Sun, Jingwen Guo, Yan Li, Yue Yan, Yiting Gong, Jiayi Lin, Yuan Hu, Jinmei Jin, Bei Wang, Hongzhuan Chen, Lijun Zhang, Weidong Zhang, Xin Luan · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2024.101915 · 被引用次数：24 · 研究领域：Ferroptosis and cancer prognosis、Epigenetics and DNA Methylation、Cancer-related gene regulation

Tumor-associated neutrophils (TANs) play a critical role in the progression and prognosis of triple-negative breast cancer (TNBC), with N2-type TANs known for their pro-tumor characteristics. This study introduces CT-1, a derivative of cryptotanshinone that effectively suppresses TNBC growth while selectively reducing the proportion of N2-type TANs within tumor tissue. Notably, CT-1 induces simultaneous ferroptosis in both N2-type TANs and TNBC cells, a dual mechanism that enhances its therapeutic efficacy. The study identifies ferritin heavy chain 1 (FTH1), a key protein in iron metabolism, as the direct target of CT-1. By targeting FTH1, CT-1 facilitates the interaction between NCOA4 and ferritin, triggering ferritinophagy-mediated ferroptosis. These findings position CT-1 as a promising therapeutic agent, offering a strategy to combat TNBC by inducing ferroptosis in both N2-type TANs and cancer cells. This approach underscores the potential of FTH1 as a therapeutic target for treating TNBC. • CT-1 dual-targets N2-type TANs and TNBC cells to combat TNBC • CT-1 selectively eliminates N2-type TANs without affecting other immune cells • CT-1 induces ferritinophagy-mediated ferroptosis by targeting FTH1 • CT-1 promotes lysosomal autophagic degradation of FTH1 Liu et al. explored the efficacy and underlying mechanism of CT-1 in combating TNBC. CT-1 effectively inhibits TNBC by targeting FTH1 and facilitating the interaction between NCOA4 and ferritin, thereby triggering ferritin...