Txnip, also known as Thioredoxin interacting protein or VDUP1 (vitamin D3 upregulated protein-1), is an alpha-arrestin protein crucial for redox homeostasis in the human body. It binds to thioredoxin (TRX), inhibiting its function and expression, and is involved in multiple pathways, such as those related to glucose and lipid metabolism, apoptosis, and inflammation [3,4].

Txnip-knockout (KO) mouse models have revealed its significant roles in various disease conditions. In non-alcoholic steatohepatitis (NASH), deletion of the Txnip gene enhanced hepatic steatosis, inflammation, and fibrosis, along with impaired autophagy and fatty acid oxidation (FAO) in methionine choline-deficient (MCD) diet-fed mice. 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 and upregulated bone morphogenetic protein signaling [2]. In diabetic kidney disease, TXNIP knockout suppressed renal fibrosis and activation of mammalian target of rapamycin complex 1 (mTORC1), and restored transcription factor EB (TFEB) and autophagy activation in diabetic kidneys [5].

In conclusion, Txnip plays essential roles in regulating autophagy, fatty acid oxidation, and the osteochondrogenic switch of VSMCs, as well as in the fibrotic process of diabetic kidney disease. The Txnip KO mouse models have significantly contributed to understanding its functions in NASH, atherosclerotic calcification, and diabetic kidney disease, providing insights into potential therapeutic strategies targeting Txnip for these diseases.

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. 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/

4. Deng, Jinhai, Pan, Teng, Liu, Zaoqu, Beatson, Richard, Ng, Tony. 2023. The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control. In British journal of cancer, 129, 1877-1892. doi:10.1038/s41416-023-02442-4. https://pubmed.ncbi.nlm.nih.gov/37794178/

5. 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/