卵巢癌(Ovarian cancer, OC)是一种高度致命的妇科恶性肿瘤，通常在晚期诊断，治疗选择有限。在这里，我们证明了抗菌肽CS-piscidin显著抑制OC细胞的增殖、形成菌落并诱导细胞死亡。从机制上讲，CS-piscidin通过破坏细胞膜导致细胞坏死。此外，CS-piscidin可以激活受体相互作用蛋白激酶1 (RIPK1)，通过PARP的裂解诱导细胞凋亡。为了提高肿瘤靶向能力，我们通过在C末端添加一个短的环肽cyclo-RGDfk（CS-RGD）和在N-末端添加肉豆蔻酸甘油酯（Myr-CS-RGD）来修改CS-piscidin。我们的结果表明，虽然CS-RGD表现出比CS-piscidin更强的抗癌活性，但也会导致细胞毒性增加。相反，Myr-CS-RGD通过减少CS-RGD在正常细胞中的毒性，同时增加肽稳定性来显著提高药物的特异性。在一个同基因小鼠肿瘤模型中，Myr-CS-RGD表现出比CS-piscidin和CS-RGD更优异的抗肿瘤活性。我们的发现表明，CS-piscidin可以通过多种细胞死亡方式抑制卵巢癌，并且肉豆蔻酰化修饰是增强抗癌肽性能的有前途的策略。 ©2023. 作者。

Ovarian cancer (OC) is a highly lethal gynecological malignancy, often diagnosed at advanced stages with limited treatment options. Here, we demonstrate that the antimicrobial peptide CS-piscidin significantly inhibits OC cell proliferation, colony formation, and induces cell death. Mechanistically, CS-piscidin causes cell necrosis by compromising the cell membrane. Furthermore, CS-piscidin can activate Receptor-interacting protein kinase 1 (RIPK1) and induce cell apoptosis by cleavage of PARP. To improve tumor targeting ability, we modified CS-piscidin by adding a short cyclic peptide, cyclo-RGDfk, to the C-terminus (CS-RGD) and a myristate to the N-terminus (Myr-CS-RGD). Our results show that while CS-RGD exhibits stronger anti-cancer activity than CS-piscidin, it also causes increased cytotoxicity. In contrast, Myr-CS-RGD significantly improves drug specificity by reducing CS-RGD toxicity in normal cells while retaining comparable antitumor activity by increasing peptide stability. In a syngeneic mouse tumor model, Myr-CS-RGD demonstrated superior anti-tumor activity compared to CS-piscidin and CS-RGD. Our findings suggest that CS-piscidin can suppress ovarian cancer via multiple cell death forms and that myristoylation modification is a promising strategy to enhance anti-cancer peptide performance.© 2023. The Author(s).