Feng Li, Wu Ti-Zhi, Guo Xin-Rui, Wang Yun-Jie, Wang Xin-Jia, Liu Shao-Xuan, Zhang Rui, Ma Yi, Tan Ning-Hua, Bian Jin-Lei, Wang Zhe
State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
State Key Laboratory of Natural Medicines, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
ACS Cent Sci. 2025 Feb 10;11(2):357-370. doi: 10.1021/acscentsci.4c02188. eCollection 2025 Feb 26.
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer. Cuproptosis, a novel identified cell death form, is triggered by the direct binding of copper to lipoylated components of the tricarboxylic acid cycle. Identifying new effective drug targets and copper ionophores inducing cuproptosis for TNBC therapy is an urgent clinical need. In this study, a total of 24 resorcylic acid lactones (RALs, -), including 9 previously unreported ones, were isolated from the endophyte sp. Various assays demonstrated that pochonin D (, PoD) effectively inhibited the proliferation of TNBC cells and . Further investigations, including transcriptomics, proteomics, bioinformatics analysis, CMap, OTTER, clinical samples, and the use of PoD as molecular probe, revealed that PRDX1 is associated with cuproptosis and served as a potential target in TNBC. Mechanistically, PRDX1 was involved in the process of cuproptosis, and PoD bound to the Cys173 site of PRDX1, inhibited its enzymatic activity, and intervened with cuproptosis, thereby exerting anti-TNBC activity. Our study revealed that PRDX1 is not only a promising biomarker associated with cuproptosis but also a therapeutic target for TNBC, and PoD is a novel copper ionophore capable of inducing cuproptosis in TNBC cells by targeting PRDX1.
三阴性乳腺癌（TNBC）是一种侵袭性很强的乳腺癌亚型。铜死亡是一种新发现的细胞死亡形式，由铜直接与三羧酸循环的脂酰化成分结合引发。确定新的有效药物靶点和诱导铜死亡的铜离子载体用于TNBC治疗是临床迫切需求。在本研究中，从内生菌sp.中总共分离出24种间苯二酚内酯（RALs， - ），其中包括9种以前未报道的。各种实验表明，波乔宁D（，PoD）能有效抑制TNBC细胞和的增殖。进一步的研究，包括转录组学、蛋白质组学、生物信息学分析、CMap、OTTER、临床样本以及使用PoD作为分子探针，揭示PRDX1与铜死亡相关，并在TNBC中作为潜在靶点。机制上，PRDX1参与了铜死亡过程，PoD与PRDX1的Cys173位点结合，抑制其酶活性，并干预铜死亡，从而发挥抗TNBC活性。我们的研究表明，PRDX1不仅是与铜死亡相关的有前景的生物标志物，也是TNBC的治疗靶点，并且PoD是一种新型铜离子载体，能够通过靶向PRDX1诱导TNBC细胞发生铜死亡。
