核因子红细胞相关因子2-因子2(Nrf2)是一种传统上被认为是细胞保护者的转录因子。然而，在许多癌症中，Nrf2被持续激活并与治疗抵抗相关。 Nrf2与小肌肉腱膜纤维肉瘤Maf（sMAF）转录因子异源二聚体化，允许结合到抗氧化应答元件（ARE）并诱导Nrf2靶基因的转录。虽然转录因子历来是难以靶向的，但订钉肽已经显示出抑制这些蛋白质-蛋白质相互作用的巨大潜力。在这里，我们描述了第一个直接的细胞渗透性Nrf2/sMAF异源二聚体化抑制剂。 N1S是一种根据AlphaFold预测，基于Nrf2和sMAF MafG之间的相互作用设计的订钉肽。细胞报告基因检测结合与体外生物物理检测表明，N1S可以直接抑制Nrf2 / MafG异源二聚体化。 N1S处理降低了Nrf2依赖基因的转录，并使Nrf2依赖性癌细胞对顺铂敏感。总体而言，N1S是Nrf2成瘾癌症敏化的有希望的前导物。

Nuclear factor erythroid-related 2-factor 2 (Nrf2) is a transcription factor traditionally thought of as a cellular protector. However, in many cancers, Nrf2 is constitutively activated and correlated with therapeutic resistance. Nrf2 heterodimerizes with small musculoaponeurotic fibrosarcoma Maf (sMAF) transcription factors, allowing binding to the antioxidant responsive element (ARE) and induction of transcription of Nrf2 target genes. While transcription factors are historically challenging to target, stapled peptides have shown great promise for inhibiting these protein-protein interactions. Herein, we describe the first direct cell-permeable inhibitor of Nrf2/sMAF heterodimerization. N1S is a stapled peptide designed based on AlphaFold predictions of the interactions between Nrf2 and sMAF MafG. A cell-based reporter assay combined with in vitro biophysical assays demonstrates that N1S directly inhibits Nrf2/MafG heterodimerization. N1S treatment decreases the transcription of Nrf2-dependent genes and sensitizes Nrf2-dependent cancer cells to cisplatin. Overall, N1S is a promising lead for the sensitization of Nrf2-addicted cancers.