Liver fibrosis is a pivotal and reversible stage in the progression of chronic liver disease. However, the mechanisms underlying fibrosis reversal remain unclear, and effective diagnostic biomarkers are lacking in clinical practice. In this study, we aimed to elucidate the role and molecular mechanisms of glutathione S-transferase Mu 3 (GSTM3) in liver fibrosis reversal, and preliminarily determine whether GSTM3 can serve as a novel biomarker for liver fibrosis reversal.
Carbon tetrachloride-induced mouse models of liver fibrosis and spontaneous reversal were established. Proteomic analysis was used to identify proteins shared between liver tissue and serum that were continuously downregulated during fibrosis reversal. The expression of GSTM3 was evaluated in the livers of mice undergoing fibrosis reversal and in clinical samples from patients with liver fibrosis. Hepatic stellate cells (HSCs) were transfected with Gstm3 -silencing RNA or an overexpression plasmid to assess the effects on fibrosis markers. RNA sequencing analyses were performed, and the underlying molecular mechanisms were investigated.
Proteomic analysis revealed significantly decreased GSTM3 levels in both hepatic tissue and serum in mice undergoing fibrosis reversal, and its expression was negatively correlated with the extent of reversal. GSTM3 levels were markedly increased in the hepatic tissue and serum of patients with liver fibrosis. GSTM3 expression was upregulated in transforming growth factor-β-stimulated HSCs. GSTM3 knockdown inhibited the expression of fibrosis markers, such as collagen type I α1 and tissue inhibitor of metalloproteinase 1, whereas its overexpression promoted their expression. Mechanistic studies indicated that GSTM3 knockdown activated peroxisome proliferator-activated receptor γ (PPARγ) signaling and downregulated its downstream targets, cluster of differentiation 36 and fatty acid-binding protein 4, thereby suppressing HSC activation.
GSTM3 was identified as a novel regulator that is progressively downregulated during fibrosis reversal in mouse liver. GSTM3 knockdown promotes liver fibrosis reversal, which may be mediated by the inhibition of HSC activation via the PPARγ-FABP4-CD36 signaling pathway. Moreover, GSTM3 levels gradually increased with disease stage in the serum and liver tissue of patients with fibrosis; thus, GSTM3 may serve as a promising therapeutic target and diagnostic biomarker for liver fibrosis.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00658
The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
Follow us on X: @xiahepublishing
Follow us on LinkedIn: Xia & He Publishing Inc.
Journal of Clinical and Translational Hepatology
GSTM3 Knockdown Promotes Liver Fibrosis Reversal by Inhibiting Hepatic Stellate Cell Activation via PPARγ Signaling
25-May-2026