Osgin1-KO Mouse

Oxidative stress induced growth inhibitor 1 (OSGIN1), a tumor protein p53 (TP53)-target gene, is involved in the oxidative stress response and apoptosis regulation [1]. It also participates in multiple pathways such as NFE2 like BZIP transcription factor 2 (NFE2L2)-dependent signaling, which is crucial for its role in various biological processes and disease conditions [1]. Its study through genetic models, like KO or CKO mouse models, can unveil its precise functions.

In pancreatic ductal adenocarcinoma (PDAC) cells, OSGIN1 expression is upregulated by ferroptosis inducers in an NFE2L2-dependent manner rather than via the TP53 pathway. Genetic depletion of OSGIN1 promotes ferroptosis, indicating its role in inhibiting this form of oxidative cell death. Re-expression of OSGIN1 rescues ferroptosis resistance in NFE2L2-knockout cells both in vitro and in animal models [1]. In non-small cell lung cancer (NSCLC), OSGIN1 is highly expressed, and its knockdown inhibits cell growth and re-establishes gefitinib sensitivity. It enhances DYRK1A-mediated TUBB3 phosphorylation to modulate microtubule dynamics and promote tumor growth and gefitinib resistance through the MKK3/6-p38 signaling pathway [2]. In cigarette smoke-induced endothelial detachment relevant to plaque erosion, knockdown of OSGIN1 inhibits Nrf2-induced cell detachment [3]. In an in vitro model of COPD, PM2.5 upregulates OSGIN1 through inhibiting miR-654-5p, leading to increased autophagy and fibrosis [4]. In pancreatitis, pancreatic knockdown of Osgin1 abolishes the therapeutic effects of FXR activation on pancreatitis, while overexpression alleviates it, suggesting a protective role of the FXR-OSGIN1 axis [5]. In ovarian cancer, loss of the OSGIN1 gene promotes cancer growth and confers resistance to drug-induced ferroptosis by activating the AMPK-SLC2A3 axis [6].

In summary, OSGIN1 plays diverse and important roles in multiple disease areas including cancer, cardiovascular, and respiratory diseases. Gene knockout or knockdown models have been instrumental in revealing its functions in processes such as ferroptosis, tumor growth, cell detachment, autophagy, and fibrosis, offering potential therapeutic targets for these diseases.

References:

1. Jia, Yuanyuan, Zhang, Xinyue, Cai, Yiqing, Hu, Nanjun, Han, Leng. 2024. OSGIN1 promotes ferroptosis resistance by directly enhancing GCLM activity. In Biochemical and biophysical research communications, 740, 151015. doi:10.1016/j.bbrc.2024.151015. https://pubmed.ncbi.nlm.nih.gov/39571229/

2. Xie, Xiaomeng, Laster, Kyle Vaughn, Li, Jian, Dong, Zigang, Kim, Dong Joon. 2023. OSGIN1 is a novel TUBB3 regulator that promotes tumor progression and gefitinib resistance in non-small cell lung cancer. In Cellular and molecular life sciences : CMLS, 80, 272. doi:10.1007/s00018-023-04931-4. https://pubmed.ncbi.nlm.nih.gov/37646890/

3. Satta, Sandro, Beal, Robert, Smith, Rhys, Newby, Andrew C, White, Stephen J. . A Nrf2-OSGIN1&2-HSP70 axis mediates cigarette smoke-induced endothelial detachment: implications for plaque erosion. In Cardiovascular research, 119, 1869-1882. doi:10.1093/cvr/cvad022. https://pubmed.ncbi.nlm.nih.gov/36804807/

4. Tang, Xiying, Zhu, Huanhuan, Zhou, Meiyu, Zhang, Zhengdong, Chu, Haiyan. 2024. OSGIN1 regulates PM2.5-induced fibrosis via mediating autophagy in an in vitro model of COPD. In Toxicology letters, 401, 35-43. doi:10.1016/j.toxlet.2024.09.003. https://pubmed.ncbi.nlm.nih.gov/39260748/

5. Zheng, Yufan, Sun, Wenrui, Wang, Zhengyang, Li, Xiaobo, Sun, Ning. 2022. Activation of Pancreatic Acinar FXR Protects against Pancreatitis via Osgin1-Mediated Restoration of Efficient Autophagy. In Research (Washington, D.C.), 2022, 9784081. doi:10.34133/2022/9784081. https://pubmed.ncbi.nlm.nih.gov/36405253/

6. Deng, Mengqi, Tang, Fan, Chang, Xiangyu, He, Junqi, Miao, Jinwei. 2025. A targetable OSGIN1 - AMPK - SLC2A3 axis controls the vulnerability of ovarian cancer to ferroptosis. In NPJ precision oncology, 9, 15. doi:10.1038/s41698-024-00791-8. https://pubmed.ncbi.nlm.nih.gov/39809873/