Yin-Dan-Ping-Gan Capsule Mitigates CCL4-Induced Liver Fibrosis via Regulating PPAR γ/GPX4 Signaling and Suppressing Ferroptosis

TL;DR

Yin-Dan-Ping-Gan Capsule reduces liver fibrosis by regulating a key pathway that controls cell death and oxidative stress.

Contribution

The study reveals a novel mechanism by which Yin-Dan-Ping-Gan Capsule mitigates liver fibrosis through the PPARγ/GPX4 pathway and ferroptosis suppression.

Findings

Yin-Dan-Ping-Gan Capsule reduced liver fibrosis and improved liver function in a CCL4-induced mouse model.

The capsule inhibited oxidative stress and ferroptosis by regulating the PPARγ/GPX4 signaling pathway.

Network pharmacology and proteomics identified ferroptosis and PPAR pathways as central to the anti-fibrotic effects of the capsule.

Abstract

Background: Liver fibrosis is a major global public health issue that is only getting worse. The underlying molecular mechanisms of Yindanpinggan Capsule (YDPG), a traditional Chinese medication, are still unknown, although it has shown notable effectiveness in treating fibrosis and other forms of liver injury. Methods: To evaluate the impact of YDPG on liver fibrosis, a mouse model of liver damage caused by carbon tetrachloride (CCL4) was used. Proteomics, deep learning, network pharmacology, and later biological process validation using Western blot were used to elucidate the possible mechanism of YDPG in reducing liver damage. Results: Following YDPG treatment, we observed a decrease in the fibrosis index and an improvement in liver function. Network pharmacology, deep learning, and proteomics collectively identified the ferroptosis and peroxisome proliferator-activated receptor (PPAR) signaling pathways as pivotal in the anti-fibrosis effects of YDPG on the liver. Further experimental results showed that YDPG inhibited Malondialdehyde (MDA) and Fe2+ content and increased Glutathione (GSH) activity in fibrotic liver. Mechanistically, both SLC7A11/GSH pathway-mediated ferroptosis and oxidative stress up-regulated by the PPAR γ/GPx4 pathway were alleviated following YDPG treatment. Conclusions: Our present study corroborates that YDPG limits the progression of liver fibrosis by regulating the PPARγ-GPX4-ferroptosis pathway. These results indicate that YDPG could be a potential medication for hepatic fibrosis.

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