Txnip, also known as thioredoxin interacting protein or VDUP1 (vitamin D3 upregulated protein-1), is an alpha-arrestin protein essential for redox homeostasis in the human body. It binds to thioredoxin (TRX) and inhibits TRX function and expression. Txnip is involved in multiple pathways, including those related to autophagy, fatty acid oxidation, and inflammation, and plays a crucial role in various biological processes and disease conditions. Genetic models, such as gene knockout (KO) mouse models, have been instrumental in studying its functions [4].

In non-alcoholic steatohepatitis (NASH), deletion of the Txnip gene in mice enhanced hepatic steatosis, inflammation, and fibrosis, along with impaired autophagy and fatty acid oxidation (FAO). Mechanistically, Txnip directly interacted with and positively regulated p-PRKAA, leading to inactivation of MTORC1 and nuclear translocation of TFEB, which promoted autophagy [1]. In atherosclerotic calcification, Txnip-/-mice showed increased atherosclerotic lesion calcification and collagen deposition. Single-cell RNA-sequencing analysis identified modulated VSMC and osteochondrogenic clusters, with the osteochondrogenic cluster expanded in Txnip-/-mice. Suppression of Txnip in cultured VSMCs accelerated osteodifferentiation [2]. In diabetic cataract, high glucose stress induced TXNIP/NLRP3 inflammasome activation in human lens epithelial cells and rat lenses, while SIRT1 inhibited this activation [3]. In intestinal ischemia-reperfusion injury, metformin protected against injury by suppressing Txnip expression and the interaction between Txnip and NLRP3 [5]. In acute lung injury, FTO deficiency alleviated LPS-induced injury via the Txnip/NLRP3 pathway-mediated alveolar epithelial cell pyroptosis [6]. In diabetic kidney disease, Txnip knockout suppressed renal fibrosis and mTORC1 activation, and restored TFEB and autophagy activation [7].

In conclusion, Txnip is a key regulator involved in multiple biological processes such as autophagy, lipid metabolism, and inflammation. Txnip KO mouse models have revealed its significance in diseases like NASH, atherosclerotic calcification, diabetic cataract, intestinal ischemia-reperfusion injury, acute lung injury, and diabetic kidney disease. Understanding Txnip's functions through these models provides insights into disease mechanisms and potential therapeutic strategies.

References:

1. Park, Hee-Seon, Song, Ji-Won, Park, Jin-Ho, Won, Young-Suk, Kwon, Hyo-Jung. 2020. TXNIP/VDUP1 attenuates steatohepatitis via autophagy and fatty acid oxidation. In Autophagy, 17, 2549-2564. doi:10.1080/15548627.2020.1834711. https://pubmed.ncbi.nlm.nih.gov/33190588/

2. Woo, Sang-Ho, Kyung, Dongsoo, Lee, Seung Hyun, Choi, Jae-Hoon, Kim, Dae-Yong. 2022. TXNIP Suppresses the Osteochondrogenic Switch of Vascular Smooth Muscle Cells in Atherosclerosis. In Circulation research, 132, 52-71. doi:10.1161/CIRCRESAHA.122.321538. https://pubmed.ncbi.nlm.nih.gov/36448450/

3. Lian, Lili, Le, Zhenmin, Wang, Zhenzhen, Zheng, Qinxiang, Ren, Yueping. . SIRT1 Inhibits High Glucose-Induced TXNIP/NLRP3 Inflammasome Activation and Cataract Formation. In Investigative ophthalmology & visual science, 64, 16. doi:10.1167/iovs.64.3.16. https://pubmed.ncbi.nlm.nih.gov/36881408/

4. Pan, Min, Zhang, Fengping, Qu, Kai, Liu, Chang, Zhang, Jingyao. 2022. TXNIP: A Double-Edged Sword in Disease and Therapeutic Outlook. In Oxidative medicine and cellular longevity, 2022, 7805115. doi:10.1155/2022/7805115. https://pubmed.ncbi.nlm.nih.gov/35450411/

5. Jia, Yifan, Cui, Ruixia, Wang, Cong, Liu, Chang, Zhang, Jingyao. 2020. Metformin protects against intestinal ischemia-reperfusion injury and cell pyroptosis via TXNIP-NLRP3-GSDMD pathway. In Redox biology, 32, 101534. doi:10.1016/j.redox.2020.101534. https://pubmed.ncbi.nlm.nih.gov/32330868/

6. Xie, Wei-Ming, Su, Wei, Liu, Xin-Yu, Li, Zhanfei, Li, Tianyu. . FTO Deficiency Alleviates LPS-induced Acute Lung Injury by TXNIP/NLRP3-mediated Alveolar Epithelial Cell Pyroptosis. In American journal of respiratory cell and molecular biology, 70, 351-363. doi:10.1165/rcmb.2023-0251OC. https://pubmed.ncbi.nlm.nih.gov/38271683/

7. Du, Yunxia, Wu, Ming, Song, Shan, Bian, Yawei, Shi, Yonghong. 2024. TXNIP deficiency attenuates renal fibrosis by modulating mTORC1/TFEB-mediated autophagy in diabetic kidney disease. In Renal failure, 46, 2338933. doi:10.1080/0886022X.2024.2338933. https://pubmed.ncbi.nlm.nih.gov/38616177/