Txndc5, also known as endothelial protein-disulfide isomerase (Endo-PDI) and endoplasmic reticulum protein 46 (ERp46), is a member of the protein disulfide isomerase (PDI) family. It is confined to the endoplasmic reticulum via the KDEL retention signal. Txndc5 can promote disulfide bond formation and rearrangement, ensuring proper protein folding. It has three Trx-like domains that can act independently to introduce disulfide bonds rapidly and disorderly. It plays crucial roles in regulating cell proliferation, apoptosis, migration, and antioxidative stress [1,4,5,6].

In renal fibrosis, fibroblast-specific deletion of Txndc5 in mice mitigated the progression of established kidney fibrosis, suggesting that Txndc5 promotes renal fibrosis by enforcing TGF-β signaling in kidney fibroblasts [2]. In liver fibrosis, HSC-specific deletion of Txndc5 reverted established liver fibrosis in mice. Txndc5 promotes liver fibrosis through redox-dependent HSC activation, proliferation, and excessive extracellular matrix production [3].

In conclusion, Txndc5 is essential for proper protein folding and regulation of various cellular processes. The gene knockout (KO) and conditional knockout (CKO) mouse models have revealed its promoting role in organ fibrosis, including renal and liver fibrosis. These findings suggest Txndc5 as a potential therapeutic target for treating fibrosis-related diseases.

References:

1. Wang, Xueling, Li, Haoran, Chang, Xiaotian. 2022. The role and mechanism of TXNDC5 in diseases. In European journal of medical research, 27, 145. doi:10.1186/s40001-022-00770-4. https://pubmed.ncbi.nlm.nih.gov/35934705/

2. Chen, Yen-Ting, Jhao, Pei-Yu, Hung, Chen-Ting, Lin, Shuei-Liong, Yang, Kai-Chien. . Endoplasmic reticulum protein TXNDC5 promotes renal fibrosis by enforcing TGF-β signaling in kidney fibroblasts. In The Journal of clinical investigation, 131, . doi:10.1172/JCI143645. https://pubmed.ncbi.nlm.nih.gov/33465051/

3. Hung, Chen-Ting, Su, Tung-Hung, Chen, Yen-Ting, Lin, Shuei-Liong, Yang, Kai-Chien. 2021. Targeting ER protein TXNDC5 in hepatic stellate cell mitigates liver fibrosis by repressing non-canonical TGFβ signalling. In Gut, 71, 1876-1891. doi:10.1136/gutjnl-2021-325065. https://pubmed.ncbi.nlm.nih.gov/34933915/

4. Jiao, Mingxia, Zhang, Yeyong, Song, Xie, Xu, Bing. 2024. The role and mechanism of TXNDC5 in disease progression. In Frontiers in immunology, 15, 1354952. doi:10.3389/fimmu.2024.1354952. https://pubmed.ncbi.nlm.nih.gov/38629066/

5. Bidooki, Seyed Hesamoddin, Navarro, María A, Fernandes, Susana C M, Osada, Jesus. 2024. Thioredoxin Domain Containing 5 (TXNDC5): Friend or Foe? In Current issues in molecular biology, 46, 3134-3163. doi:10.3390/cimb46040197. https://pubmed.ncbi.nlm.nih.gov/38666927/

6. Horna-Terrón, Elena, Pradilla-Dieste, Alberto, Sánchez-de-Diego, Cristina, Osada, Jesús. 2014. TXNDC5, a newly discovered disulfide isomerase with a key role in cell physiology and pathology. In International journal of molecular sciences, 15, 23501-18. doi:10.3390/ijms151223501. https://pubmed.ncbi.nlm.nih.gov/25526565/