Neratinib 是一种小分子酪氨酸激酶抑制剂 (TKI)，可与人表皮生长因子受体 1、2 和 4 (HER1/2/4) 不可逆地结合，是一种经批准的针对 HER2 扩增或过度表达患者的延长辅助治疗。 HER2 阳性）乳腺癌。接受来那替尼治疗的患者可能会出现轻度至重度的肠道毒性症状，包括腹痛和腹泻。尽管是肠道健康中非常普遍的并发症，但来那替尼引起的肠道损伤（尤其是结肠损伤）的生物学过程仍不清楚。实时定量聚合酶链反应（RT-qPCR）和组织学相结合来研究以下因素的影响：以及由每日服用 neratinib（50 mg/kg）持续 28 天的雌性 Albino Wistar 大鼠收集的结肠组织中 neratinib 诱导的细胞死亡类型。此外，利用先前发布的人胶质母细胞瘤 SF268 细胞系和胶质母细胞瘤 T895 异种移植物以及小鼠 TBCP1 乳腺癌细胞系的批量 RNA 测序和 CRISPR 筛选数据集来阐明来那替尼诱导细胞死亡的潜在机制。 结肠上皮损伤的严重程度远端结肠比近端结肠更明显，尤其是表面衬里结肠细胞的变性和免疫细胞的浸润。测序显示，细胞凋亡基因特征在neratinib处理的SF268细胞中富集，而铁死亡基因特征在neratinib处理的TBCP1细胞和T895异种移植物中富集。然而，我们发现，铁死亡（但不太可能发生细胞凋亡）是来那替尼治疗的大鼠结肠损伤的潜在组织病理学特征。铁死亡是来那替尼诱导的结肠损伤的潜在特征，针对控制来那替尼诱导的铁死亡的分子机制可能代表了一种潜在的组织病理学特征。改善肠道毒性症状的有吸引力的治疗方法。© 2024。作者。

Neratinib, a small-molecule tyrosine kinase inhibitor (TKI) that irreversibly binds to human epidermal growth factor receptors 1, 2 and 4 (HER1/2/4), is an approved extended adjuvant therapy for patients with HER2-amplified or -overexpressed (HER2-positive) breast cancers. Patients receiving neratinib may experience mild-to-severe symptoms of gut toxicity including abdominal pain and diarrhoea. Despite being a highly prevalent complication in gut health, the biological processes underlying neratinib-induced gut injury, especially in the colon, remains unclear.Real-time quantitative polymerase chain reaction (RT-qPCR) and histology were integrated to study the effect of, and type of cell death induced by neratinib on colonic tissues collected from female Albino Wistar rats dosed with neratinib (50 mg/kg) daily for 28 days. Additionally, previously published bulk RNA-sequencing and CRISPR-screening datasets on human glioblastoma SF268 cell line and glioblastoma T895 xenograft, and mouse TBCP1 breast cancer cell line were leveraged to elucidate potential mechanisms of neratinib-induced cell death.The severity of colonic epithelial injury, especially degeneration of surface lining colonocytes and infiltration of immune cells, was more pronounced in the distal colon than the proximal colon. Sequencing showed that apoptotic gene signature was enriched in neratinib-treated SF268 cells while ferroptotic gene signature was enriched in neratinib-treated TBCP1 cells and T895 xenograft. However, we found that ferroptosis, but less likely apoptosis, was a potential histopathological feature underlying colonic injury in rats treated with neratinib.Ferroptosis is a potential feature of neratinib-induced colonic injury and that targeting molecular machinery governing neratinib-induced ferroptosis may represent an attractive therapeutic approach to ameliorate symptoms of gut toxicity.© 2024. The Author(s).