Ireb2-KO Mouse

IREB2, also known as iron responsive element binding protein 2, plays a crucial role in iron metabolism. It binds to iron-responsive elements, regulating the translation and stability of mRNAs involved in iron homeostasis pathways. Its dysregulation can impact biological processes related to iron balance, which is of great significance for normal cellular function and is associated with various diseases [1,2,3,4,5,6,7].

In the context of chronic obstructive pulmonary disease (COPD), m6A-modified circSAV1 forms an RNA-protein ternary complex with YTHDF1 and IREB2, facilitating IREB2 mRNA translation. Elevated IREB2 protein levels disrupt iron homeostasis, leading to the accumulation of a labile iron pool and lipid peroxidation, ultimately triggering ferroptosis in lung epithelial cells. This ferroptosis contributes to COPD progression [1]. A meta-analysis also showed that certain IREB2 variants (such as rs2568494, rs2656069, rs10851906) are associated with the susceptibility to COPD [2]. In non-small-cell lung cancer, knockdown of IREB2 notably weakens curcumin-induced ferroptosis and anti-tumor effect, indicating its role in curcumin-induced ferroptosis [4]. In colorectal cancer cells, miR-19a suppresses ferroptosis by targeting IREB2 [7].

In conclusion, IREB2 is essential in regulating iron homeostasis, and its dysregulation is linked to diseases like COPD, non-small-cell lung cancer, and colorectal cancer. Research on IREB2, especially through functional studies in relevant disease models, helps in understanding the molecular mechanisms of these diseases and may provide potential therapeutic targets.

References:

1. Xia, Haibo, Wu, Yan, Zhao, Jing, Bian, Tao, Liu, Qizhan. 2023. N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2. In Cell death and differentiation, 30, 1293-1304. doi:10.1038/s41418-023-01138-9. https://pubmed.ncbi.nlm.nih.gov/36828914/

2. Zeng, Qiaoli, Chen, Qikang, Zou, Dehua, Wang, Yajun, Ma, Guoda. 2020. Different Associations Between the IREB2 Variants and Chronic Obstructive Pulmonary Disease Susceptibility. In Frontiers in genetics, 11, 598053. doi:10.3389/fgene.2020.598053. https://pubmed.ncbi.nlm.nih.gov/33304392/

3. Qin, Xia, Zhang, Jun, Wang, Bin, Zou, Zhen, Yu, Chao. 2021. Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells. In Autophagy, 17, 4266-4285. doi:10.1080/15548627.2021.1911016. https://pubmed.ncbi.nlm.nih.gov/33843441/

4. Tang, Xin, Ding, Hui, Liang, Maoli, Zhang, Jing, Cao, Jie. 2021. Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy. In Thoracic cancer, 12, 1219-1230. doi:10.1111/1759-7714.13904. https://pubmed.ncbi.nlm.nih.gov/33656766/

5. Zhu, Ting, Xiao, Zhuoyu, Yuan, Haoyu, Liu, Cundong, Zhou, Junhao. 2022. ACO1 and IREB2 downregulation confer poor prognosis and correlate with autophagy-related ferroptosis and immune infiltration in KIRC. In Frontiers in oncology, 12, 929838. doi:10.3389/fonc.2022.929838. https://pubmed.ncbi.nlm.nih.gov/36059676/

6. Shao, Min, Cheng, Haipeng, Li, Xiaohong, Zhou, Yan, Luo, Ziqiang. 2024. Abnormal mitochondrial iron metabolism damages alveolar type II epithelial cells involved in bleomycin-induced pulmonary fibrosis. In Theranostics, 14, 2687-2705. doi:10.7150/thno.94072. https://pubmed.ncbi.nlm.nih.gov/38773980/

7. Fan, Hongwei, Ai, Rong, Mu, Suen, Guo, Zhengrong, Liu, Lin. . MiR-19a suppresses ferroptosis of colorectal cancer cells by targeting IREB2. In Bioengineered, 13, 12021-12029. doi:10.1080/21655979.2022.2054194. https://pubmed.ncbi.nlm.nih.gov/35599631/