The role of ferroptosis mediated by Bmal1/Nrf2 in nicotine -induce injury of BTB integrity

• Published in: Free radical biology & medicine Vol. 200; pp. 26 - 35
• Main Authors: Zhang, Zelin, Cheng, Jianyong, Yang, Li, Li, Xiaoya, Hua, Rongmao, Xu, Dejun, Jiang, Zhongliang, Li, Qingwang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2023
• Subjects: Animals; Antioxidants - pharmacology; Bmal1; Circadian rhythm; Ferroptosis; Ferroptosis - genetics; Iron - metabolism; Male; Mice; NF-E2-Related Factor 2 - metabolism; Nicotine; Nicotine - toxicity; Redox homeostasis; Seeds - metabolism; Ferroptosis; Circadian rhythm; Redox homeostasis; Bmal1; Nicotine
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.02.024

Nicotine has shown the toxic effects on male reproductive system, and testicular damage is associated with ferroptosis, which is a non-apoptotic regulated cell death driven by iron-dependent lipid peroxidation. However, the role of nicotine on ferroptosis of testicular cells is largely elusive. In the present study, we showed that nicotine destroyed blood-testis barrier (BTB) by interfering with the circadian rhythm of BTB-related factors (ZO-1, N-Cad, Occludin and CX-43) and induced ferroptosis, as reflected via increased clock-control levels of lipid peroxide and decreased ferritin and GPX4, which involved in the circadian. Inhibition of ferroptosis with Fer-1 alleviated nicotine-induced injury of BTB and impaired sperm in vivo. Mechanically, we uncover that the core molecular clock protein, Bmal1, regulates the expression of Nrf2 via direct E-box binding to its promoter to regulate its activity, and nicotine decreases the transcription of Nrf2 through Bmal1 and inactivates Nrf2 pathway and its downstream antioxidant gene, which leads to the imbalance of redox state and ROS accumulation. Intriguingly, nicotine induced lipid peroxidation and subsequent ferroptosis by Bmal1-mediated Nrf2. In conclusion, our study reveals a clear role for the molecular clock in controlling Nrf2 in testis to mediate the ferroptosis induced by nicotine. These findings provide a potential mechanism to prevent smoking and/or cigarette smoke-induced male reproductive injury. [Display omitted] •Nicotine interfered with the rhythmic expression of BTB-related proteins, leading to BTB injury.•Nicotine induced BTB damage by causing the ferroptosis in the testis.•Nicotine decreases the transcription of Nrf2 through Bmal1 and inactivates Nrf2 pathway and its downstream antioxidant gene.•Nicotine contributed to ferroptosis via inactivation of the Bmal1/Nrf2 pathway.