Published online May 28, 2023. doi: 10.3748/wjg.v29.i20.3103
Peer-review started: February 6, 2023
First decision: March 21, 2023
Revised: April 1, 2023
Accepted: April 24, 2023
Article in press: April 24, 2023
Published online: May 28, 2023
Processing time: 109 Days and 1 Hours
The transforming growth factor β (TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type II receptor (TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.
To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.
Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8 (CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.
We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine (DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.
DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.
Core Tip: An effective and safe drug for treating liver fibrosis is urgently needed in current clinical practice. Here, we investigated and discovered that dihydroergotamine (DHE) could alleviate liver fibrosis by specific binding of transforming growth factor β type II receptor (TGFβR2) to disrupt the binding of TGFβR2 with TGFβ1, and ultimately suppressing its downstream TGFβ signaling pathway. DHE may be an effective anti-liver fibrosis drug, which could be employed in liver cirrhotic patients.