Kai-Chien Yang, MD, PhD
Professor at the Graduate Institute of Pharmacology, College of Medicine, National Taiwan University
Fibrosis-related conditions pose a significant global health challenge, causing substantial suffering and death. Fibrosis is characterized by the excessive buildup of extracellular matrix in areas of tissue damage, leading to distorted tissue structure, reduced function, and eventual organ failure. Currently, there is a lack of effective drug treatments specifically aimed at combating fibrosis. This underscores the pressing necessity to discover new targets for drug development against organ fibrosis.
Using an approach of combined system biology and transcriptome profiling of human/mouse fibrotic tissue, we identified an ER protein thioredoxin domain containing 5 (TXNDC5) as a potentially important mediator of tissue fibrosis. We conducted a series of in vitro and in vivo experiments to determine the molecular mechanisms by which TXNDC5 mediates the development of organ fibrosis (Figure 1).
TXNDC5 was found to be both required and sufficient to promote organ (heart, lung, kidney and liver) fibrosis and disturbed flow-induced atherosclerosis. TXNDC5 promotes tissue fibrosis through enhancing the folding and stability of TGFBR1 and extracellular matrix (ECM) proteins, leading to the augmentation of fibrogenic TGFβ signaling, fibroblast activation and ECM production. TGFβ induces TXNDC5 upregulation in tissue fibroblasts through increased ER stress level and ATF6-mediated transcriptional control. Conditional knockout of TXNDC5 in tissue fibroblasts significantly mitigates cardiac, lung, kidney and liver fibrosis in response to injury (Figure 2).
In addition to its role in organ fibrosis, we discovered that TXNDC5 is also induced in arterial endothelial cells in response to disturbed flow under the regulation of mechanical sensing transcription factor KLF2, leading to endothelial dysfunction and atherogenesis by downregulating eNOS through HSF1-HSP90 signaling axis. Conditional knockout of endothelial TXNDC5 and treatment with TXNDC5-targeting CRISPR-nanoparticles both mitigates atherosclerosis in vivo (Figure 3).
This series of investigations identified a critical yet previously unidentified function of ER protein TXNDC5 in the pathogenesis of organ fibrosis and atherosclerosis. Targeting TXNDC5 can be a novel and powerful therapeutic approach against fibrosis-related organ dysfunction and atherogenesis. We are currently developing novel pharmaceutical agents that specifically target TXNDC5, aiming to become first-in-class therapeutics for organ fibrosis and atherosclerosis.
Figure 1. TXNDC5 contributes critically to the development of organ fibrosis and atherosclerosis through its PDI activity
Figure 2. A concise overview of how TXNDC5 promotes the development of organ fibrosis at the molecular level (Adapted from J Biomed Sci. 2022 Sep 2;29(1):63.)
Figure 3. Molecular mechanisms by which TXNDC5 mediates flow-dependent endothelial dysfunction and atheroslerosis