胚胎形态因子Nodal的再表达已在多种恶性肿瘤中观察到。迄今为止，关于Nodal在结肠直肠癌（CRC）中的作用的研究仍然有限。铁死亡对CRC的进展至关重要，它是由细胞氧化还原失衡引起的，其特征是脂质过氧化。在这里，我们观察到Nodal增强了CRC细胞在体内和体外的增殖率、运动性、侵袭性和上皮间充质转化（EMT）。值得注意的是，Nodal过表达诱导了单不饱和脂肪酸的合成并增加了脂质不饱和程度。Nodal沉默导致CRC细胞脂质过氧化增加。至少部分地抑制Stearoyl-辅酶A脱饱和酶1（SCD1）的活性可以消除Nodal过表达细胞对RSL3诱导的铁死亡的抵抗作用。在机制上，SCD1被Smad2/3信号通路的激活转录上调，以应对Nodal过表达。在CRC组织中观察到显著的Nodal和SCD1上调，并且与CRC转移和不良临床结果有关。此外，针对Nodal的牛血清白蛋白纳米颗粒/si-Nodal纳米复合物对CRC进展和转移具有抗肿瘤作用。本研究阐明了Nodal在CRC发展中的作用，并揭示了一个针对Nodal的潜在基因治疗策略，以改善CRC治疗。©2023.作者。

Re-expression of an embryonic morphogen, Nodal, has been seen in several types of malignant tumours. By far, studies about Nodal's role in colorectal cancer (CRC) remain limited. Ferroptosis is essential for CRC progression, which is caused by cellular redox imbalance and characterized by lipid peroxidation. Herein, we observed that Nodal enhanced CRC cell's proliferative rate, motility, invasiveness, and epithelial-mesenchymal transition (EMT) in vivo and in vitro. Notably, Nodal overexpression induced monounsaturated fatty acids synthesis and increased the lipid unsaturation level. Nodal knockdown resulted in increased CRC cell lipid peroxidation. Stearoyl-coenzyme A desaturase 1 (SCD1) inhibition at least partially abolished the resistance of Nodal-overexpressing cells to RSL3-induced ferroptosis. Mechanistically, SCD1 was transcriptionally up-regulated by Smad2/3 pathway activation in response to Nodal overexpression. Significant Nodal and SCD1 up-regulation were observed in CRC tissues and were associated with CRC metastasis and poor clinical outcomes. Furthermore, bovine serum albumin nanoparticles/si-Nodal nanocomplexes targeting Nodal had anti-tumour effects on CRC progression and metastasis. This research elucidated the role of Nodal in CRC development and revealed a potential gene-based therapeutic strategy targeting Nodal for improving CRC treatment.© 2023. The Author(s).