Provincial Key Laboratory for Developmental Biology and Neurosciences, Key Laboratory of Optoelectronic Science and Technology for Medicine of Ministry of Education, College of Life Sciences, Fujian Normal University, No.8, Shangsan Road, Fuzhou, 350007, China.
Sci Rep. 2023 Apr 21;13(1):6528. doi: 10.1038/s41598-023-33848-y.
Irinotecan is a topoisomerase I inhibitor which has been widely used to combat several solid tumors, whereas irinotecan therapy can induce liver injury. Liver injury generally leads to tissue hypoxia, and hypoxia-inducible factor-1α (HIF-1α), a pivotal transcription factor, mediates adaptive pathophysiological responses to lower oxygen condition. Previous studies have reported a relationship between HIF-1α and autophagy, and autophagy impairment is a common characteristic in a variety of diseases. Here, irinotecan (50 mg/kg) was employed on mice, and HepG2 and L-02 cells were cultured with irinotecan (10, 20 and 40 μM). In vivo study, we found that irinotecan treatment increased final liver index, serum aminotransferase level and hepatic lipid accumulation. Impaired autophagic flux and activation of HIF-1α/BNIP3 pathway were also demonstrated in the liver of irinotecan-treated mice. Moreover, irinotecan treatment significantly deteriorated hepatic oxidative stress, evidenced by increased MDA and ROS contents, as well as decreased GSH-Px, SOD and CAT contents. Interestingly, protein levels of NLRP3, cleaved-caspase 1 and IL-1β were enhanced in the liver of mice injected with irinotecan. In vitro study, irinotecan-treated HepG2 and L-02 cells also showed impaired autophagic flux, while HIF-1α inhibition efficaciously removed the accumulated autophagosomes induced by irinotecan. Additionally, irinotecan treatment aggravated lipid accumulation in HepG2 and L-02 cells, and HIF-1α inhibition reversed the effect of irinotecan. Furthermore, HIF-1α inhibition weakened irinotecan-induced NLRP3 inflammasome activation in HepG2 cells. Taken together, our results suggest that irinotecan induces liver injury by orchestrating autophagy via HIF-1α/BNIP3 pathway, and HIF-1α inhibition could alleviate irinotecan-induced lipid accumulation in HepG2 and L-02 cells, which will provide a new clue and direction for the prevention of side effects of clinical chemotherapy drugs.
伊立替康是一种拓扑异构酶 I 抑制剂，已广泛用于治疗多种实体瘤，而伊立替康治疗可引起肝损伤。肝损伤通常导致组织缺氧，缺氧诱导因子-1α（HIF-1α）是一种关键的转录因子，介导对低氧条件的适应性病理生理反应。先前的研究报道了 HIF-1α与自噬之间的关系，自噬损伤是多种疾病的共同特征。在这里，我们使用 50mg/kg 的伊立替康处理小鼠，并使用伊立替康（10、20 和 40μM）培养 HepG2 和 L-02 细胞。在体内研究中，我们发现伊立替康处理增加了终末肝指数、血清转氨酶水平和肝脂质堆积。在伊立替康处理的小鼠肝脏中，也观察到自噬流受损和 HIF-1α/BNIP3 通路的激活。此外，伊立替康处理显著加重了肝氧化应激，表现为 MDA 和 ROS 含量增加，以及 GSH-Px、SOD 和 CAT 含量降低。有趣的是，在注射伊立替康的小鼠肝脏中，NLRP3、裂解型 caspase 1 和 IL-1β 的蛋白水平升高。在体外研究中，伊立替康处理的 HepG2 和 L-02 细胞也显示自噬流受损，而 HIF-1α 抑制有效地去除了伊立替康诱导的积累自噬体。此外，伊立替康处理加重了 HepG2 和 L-02 细胞中的脂质堆积，而 HIF-1α 抑制逆转了伊立替康的作用。此外，HIF-1α 抑制减弱了伊立替康诱导的 HepG2 细胞中 NLRP3 炎性小体的激活。总之，我们的结果表明，伊立替康通过 HIF-1α/BNIP3 通路调节自噬诱导肝损伤，HIF-1α 抑制可减轻伊立替康诱导的 HepG2 和 L-02 细胞中的脂质堆积，这为预防临床化疗药物的副作用提供了新的线索和方向。
