Multidrug resistance (MDR) is a significant challenge in cancer treatment, with limited effective strategies available. Neuropilin-1 (NRP1) is emerging as a potential therapeutic target for overcoming drug resistance, but its role in MDR and the identification of potential inhibitors require further exploration. In this study, we investigated the role of NRP1 in MDR and identifies potential inhibitors targeting NRP1. Elevated NRP1 expression was observed in oxaliplatin (OXP)-resistant HCT116 (HCT116/L) and cisplatin (DDP)-resistant A549 cells (A549/DDP). Virtual screening and biological assays identified pitavastatin (Ptv) as a potent NRP1 inhibitor that restored chemosensitivity in resistant cells both in vitro and in vivo . Mechanistic studies revealed that Ptv directly binds to NRP1, promotes degradation of Zinc finger X-chromosomal protein (ZFX), and disrupts the NRP1-ZFX axis to reverse MDR. This study provides promising prospects for targeting the NRP1-ZFX axis as a therapeutic strategy for MDR and highlights the potential clinical application of Ptv in diseases involving NRP1.
Han Yuheng,Ouyang Xinxing,Chen Yao,Lai Shujing,Sun Hongxiang,Wu Ningbo,Ruan Chun,Lu Limin,Su Bing
It is well documented that the neonatal thymus-derived (neonatal-TD) regulatory T cells (Treg) are essential to prevent lethal autoimmune diseases and allergies, and neonatal and adult thymus possesses distinct output potentials for naïve T cells, including Treg. However, the molecular features and detailed functional differences between neonatal-TD and adult thymus-derived (adult-TD) T cells in terms of their ability to maintain immune homeostasis during long-term environmental influences are still largely unknown, partially due to the lack of appropriate animal models to precisely trace these cells at specific time points. In this study, neonatal-TD and adult-TD CD4+ T cells from the spleen and Peyer's patches were traced for 9 weeks by a T cell origin-time tracing mouse model and analysed by single-cell RNA sequencing. More Treg but fewer naïve T cells were found in neonatal-TD CD4+ T cells from both tissues than those from adult-TD counterparts. Interestingly, the neonatal-TD Treg in both the spleen and Peyer's patches exhibited augmented expression of Foxp3, Gata3, Ctla4, Icos, Il2ra, Tgfb1, and Nrp1, as well as enriched Gene Ontology terms like T cell activation and tolerance induction, indicating an enhanced immunosuppressive function. These results were further confirmed by flow cytometry analysis and in vitro immune suppression assays. Flow cytometry also revealed a significantly higher proportion of neonatal-TD Treg in total Treg than that of adult-TD counterparts, suggesting the longer lifespan of neonatal-TD Treg. To investigate the intrinsic features of neonatal-TD and adult-TD CD4+ T cells, a shortened tracing time was performed. Surprisingly, the neonatal-TD and adult-TD CD4+ T cells had similar proportions of Treg and did not exhibit significant differences in Foxp3, Gata3, Ctla4, Icos, Il2ra, and Tgfb1 expression levels after tracing for 12 days. On the other hand, neonatal-TD Treg present an increased Nrp1 expression level compared with adult-TD counterparts, indicating the enhanced stability. Together, our work reveals that the neonatal-TD Treg are more immunosuppressive, which is likely shaped primarily by environmental factors.
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