Sunshinamide, a cyclodepsipeptide, has demonstrated significant potential in inhibiting cancer cell proliferation. Our prior research established the total synthesis and anticancer properties of sunshinamide. However, a deeper understanding of the structure–activity relationship (SAR) of sunshinamide remained imperative. In this study, we aimed to elucidate the SAR and mechanistic insights underlying sunshinamide action, both in vitro and in vivo. SAR studies confirm the crucial roles of both the bicyclic-ring and disulfide moiety in the anticancer activity of sunshinamide. Our recent findings unveil that sunshinamide targets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis, while also promoting lipid peroxidation by targeting Gpx4, rendering cancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated the effectiveness of sunshinamide in reducing tumor growth by inducing both apoptosis and ferroptosis. The dual efficacy of sunshinamide in eliciting apoptosis and ferroptosis positions it as a promising candidate for breast cancer therapy, addressing the challenge of chemoresistance.

中文翻译：

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通过 TrxR1 和 Gpx4 抑制对凋亡和铁亡途径的双重调节，破译 Sunshinamide 用于乳腺癌治疗的综合构效关系


Sunshinamide 是一种环肽，在抑制癌细胞增殖方面已显示出显着的潜力。我们之前的研究确定了 sunshinamide 的总合成和抗癌特性。然而，更深入地了解 sunshinamide 的结构-活性关系 （SAR） 仍然势在必行。在这项研究中，我们旨在阐明 sunshinamide 作用的 SAR 和机制见解，包括体外和体内。SAR 研究证实了双环和二硫键在防晒酰胺抗癌活性中的关键作用。我们最近的研究结果揭示了 sunshinamide 靶向 TrxR1，导致 ROS 产生和 ER 应激介导的细胞凋亡，同时还通过靶向 Gpx4 促进脂质过氧化，使癌细胞易患铁死亡。在体内，实验证明了 sunshinamide 通过诱导细胞凋亡和铁死亡来减少肿瘤生长的有效性。sunshinamide 在引发细胞凋亡和铁死亡方面的双重功效使其成为乳腺癌治疗的有前途的候选药物，解决了化疗耐药性的挑战。