Li Ge, Yuan Yuxia, Wu Xinhua, Wu Lixian
Department of Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou 350100, China.
Fujian Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou 350100, China.
Pharmaceutics. 2025 Apr 24;17(5):554. doi: 10.3390/pharmaceutics17050554.
Poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant efficacy in treating BRCA-mutated cancers; however, a significant proportion of patients fail to respond. Emerging evidence highlights the role of PARP in lipid metabolism, suggest-ing its modulation as a novel strategy to regulate tumor progression. In this study, lipidomics and transcriptomics analyses were conducted to elucidate the mechanisms underlying PARP inhibitor-induced ferroptosis and immune modulation in triple-negative breast cancer (TNBC). We demonstrated that the PARP inhibitor Niraparib significantly reprograms lipid metabolism in TNBC cells, marked by elevated phosphatidylethanolamine (PE) and cholesterol ester (ChE) levels. This metabolic shift was mechanistically linked to upregulation of the cholesterol transporter NPC1L1 via the PARP1-RELA-NPC1L1 signaling axis, which subsequently activated the AKT pathway. Combinatorial treatment with Niraparib and either Ezetimibe (an NPC1L1 inhibitor) or AZD5363 (an AKT inhibitor) synergistically enhanced TNBC cell death by promoting ferroptosis through glutathione depletion and lipid peroxidation. Furthermore, NPC1L1 inhibition amplified PARP inhibitor-induced immune responses, increasing CD8 T cell infiltration and cytotoxicity in tumors. In conclusion, our findings establish NPC1L1 as a critical mediator of PARP inhibitor efficacy and propose dual targeting of lipid metabolism, providing a new therapeutic approach for the combination treatment of TNBC.
聚（ADP - 核糖）聚合酶（PARP）抑制剂在治疗BRCA突变的癌症方面已显示出显著疗效；然而，相当一部分患者没有反应。新出现的证据突出了PARP在脂质代谢中的作用，表明调节PARP是调控肿瘤进展的一种新策略。在本研究中，进行了脂质组学和转录组学分析，以阐明PARP抑制剂诱导三阴性乳腺癌（TNBC）铁死亡和免疫调节的潜在机制。我们证明，PARP抑制剂尼拉帕利显著重塑TNBC细胞中的脂质代谢，其标志是磷脂酰乙醇胺（PE）和胆固醇酯（ChE）水平升高。这种代谢转变在机制上与通过PARP1 - RELA - NPC1L1信号轴上调胆固醇转运蛋白NPC1L1有关，随后激活了AKT通路。尼拉帕利与依折麦布（一种NPC1L1抑制剂）或AZD5363（一种AKT抑制剂）联合治疗通过谷胱甘肽耗竭和脂质过氧化促进铁死亡，协同增强TNBC细胞死亡。此外，抑制NPC1L1可放大PARP抑制剂诱导的免疫反应，增加肿瘤中CD8 T细胞浸润和细胞毒性。总之，我们的研究结果确定NPC1L1是PARP抑制剂疗效的关键介质，并提出对脂质代谢进行双重靶向，为TNBC的联合治疗提供了一种新的治疗方法。
