Mechanistic evaluation of a traditional herbal decoction in attenuating hepatic fibrosis via Nrf2/GPX4 pathway activation and ferroptosis inhibition

TL;DR

A traditional Chinese herbal decoction may reduce liver fibrosis by activating a protective pathway and preventing cell death linked to iron buildup.

Contribution

The study provides a mechanistic evaluation of a TCM herbal decoction's anti-fibrotic effects via Nrf2/GPX4 pathway activation and ferroptosis inhibition.

Findings

The herbal decoction reduced liver damage markers and fibrosis in rats.

The decoction increased Nrf2/GPX4 pathway activity and decreased ferroptosis.

Combining the decoction with ferroptosis inhibitors enhanced its protective effects.

Abstract

Hepatic fibrosis, a progressive fibrotic response to chronic liver injury, is characterized by excessive collagen deposition and impaired tissue repair. This pathological process leads to liver dysfunction and potential progression to irreversible cirrhosis or hepatocellular carcinoma. Currently, therapeutic options targeting the underlying mechanisms remain limited. Traditional Chinese medicine (TCM), particularly herbal decoctions, have demonstrated efficacy in the treatment of hepatic fibrosis, although the precise mechanisms remain insufficiently elucidated.

The objective of this study is to examine the mechanistic role of a TCM herbal decoction designed to promote Qi, blood circulation, and water excretion, in modulating the Nrf2/GPX4 signaling pathway and inhibiting ferroptosis in a rat model of hepatic fibrosis.

A total of 17 Sprague-Dawley rats were divided into five groups. The blank control group (Group A) comprised three rats. Hepatic fibrosis was induced in the remaining rats, which were then randomized into four groups: the untreated fibrosis (Group B), TCM-treated (Group C), TCM combined with ferroptosis inhibitor (Fer-1) (Group D), and TCM combined with Fer-1 and autophagy inhibitor (3-MA) (Group E). Groups A and B received equal volumes of normal saline. Serum and hepatic tissues were collected for analysis. Serum levels of aspartate transaminase (AST), alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), and iron were measured. Liver tissues were subjected to hematoxylin and eosin staining and Masson’s trichrome staining to assess pathological changes. Protein expression levels of solute carrier family 7 member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4) were assessed using western blot analysis.

Group B exhibited significant deterioration compared to the control group (p < 0.05), including marked hepatic lipidosis and fibrosis surrounding the hepatic portal vein. Elevated levels of AST, ALT, Fe2+, MDA, TNF-α, and collagen volume were observed (p < 0.05), along with significantly reduced expression of GPX4, Nrf2, and SLC7A11 (p < 0.05). In contrast, Groups C, D, and E demonstrated significantly decreased levels of AST, ALT, Fe2+, MDA, TNF-α, and collagen volume (p < 0.05), accompanied by increased expression of GPX4, Nrf2, and SLC7A11 (p < 0.05) when compared to Group B.

The herbal decoction demonstrated anti-fibrotic effects in a rat model of hepatic fibrosis, potentially through activation of the Nrf2/GPX4 signaling pathway and suppression of ferroptosis. These findings suggest a mechanistic basis for the observed efficacy of this TCM formulation and support its potential as a therapeutic candidate for hepatic fibrosis.

The online version contains supplementary material available at 10.1186/s41065-025-00471-y.

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