Liver fibrosis, a pathological scarring process resulting from chronic liver injury, represents a significant global health burden due to its potential progression to cirrhosis and hepatocellular carcinoma. A central driver of this process is Transforming Growth Factor-Beta (TGF-β), a cytokine that promotes the activation of hepatic stellate cells (HSCs) into collagen-producing myofibroblasts. Despite the critical role of TGF-β, no targeted anti-fibrotic drugs are currently approved for clinical use, leaving etiological control as the primary treatment strategy. This review systematically explores the therapeutic potential of inhibiting the multifaceted TGF-β signaling pathway for the treatment of liver fibrosis.
The Central Role of TGF-β in Liver Fibrogenesis
TGF-β exerts its pro-fibrotic effects through a complex network of signaling pathways. The canonical SMAD-dependent pathway is initiated when TGF-β ligands bind to transmembrane receptors (TβRII/TβRI/ALK5), leading to the phosphorylation of SMAD2/3. These proteins complex with SMAD4 and translocate to the nucleus to activate fibrogenic gene transcription. The pathway is naturally counterbalanced by inhibitory SMADs (SMAD6/7). Concurrently, TGF-β activates several SMAD-independent pathways, including PI3K/Akt, MAPK (ERK, JNK, p38), and TAK1, which synergize with SMAD signaling to enhance HSC activation, epithelial-mesenchymal transition (EMT), and extracellular matrix (ECM) production. This intricate signaling network makes TGF-β a master regulator of fibrosis, but also a challenging therapeutic target due to its dual role in both promoting fibrosis and maintaining immune homeostasis.
Diverse Therapeutic Strategies to Target TGF-β Signaling
The review categorizes and evaluates various therapeutic approaches aimed at disrupting TGF-β signaling:
Direct TGF-β Blockade: This strategy employs monoclonal antibodies (e.g., Fresolinumab/GC1008, CAT-192) that neutralize TGF-β ligands, preventing receptor binding. While showing promise in other fibrotic diseases, their application in liver fibrosis remains limited in clinical trials, partly due to concerns over systemic inhibition disrupting TGF-β's homeostatic functions.
TGF-β Receptor Inhibitors: Small-molecule kinase inhibitors, such as Galunisertib (LY2157299), target the intracellular domain of TβRI (ALK5), thereby inhibiting downstream SMAD phosphorylation. Galunisertib has demonstrated anti-fibrotic efficacy and improved overall survival in patients with hepatocellular carcinoma in clinical studies, highlighting its significant translational potential. Other inhibitors, like Vactosertib and integrin inhibitors (e.g., PLN-1474), offer more targeted approaches by focusing on specific receptors involved in TGF-β activation.
Antisense Oligonucleotides (ASOs): Molecules like Trabedersen (AP-12009) are designed to bind to TGF-β mRNA, preventing its translation. This approach offers high specificity but is still in early stages of investigation for liver diseases.
Inhibition of Downstream Signaling: Drugs like Pirfenidone and its derivative Hydronidone indirectly suppress the TGF-β/SMAD pathway. Clinical trials have shown that Hydronidone, in combination with entecavir, can significantly improve liver fibrosis in patients with chronic hepatitis B.
The Promising Role of Traditional Chinese Medicine (TCM)
A notable highlight of the review is its extensive coverage of natural products from TCM. Numerous compounds—classified as alkaloids (e.g., Piperine, Sinomenine), flavonoids (e.g., Chrysin, Quercetin), and terpenoids (e.g., Limonin, Andrographolide)—have demonstrated potent anti-fibrotic effects by modulating the TGF-β pathway. These multi-component, multi-target agents represent a rich resource for drug discovery, though most evidence remains preclinical.
Challenges and Future Perspectives
Despite the promising data, the development of TGF-β inhibitors faces considerable challenges. The primary concern is the dual nature of TGF-β signaling, which acts as a tumor suppressor in early stages but promotes progression in advanced disease. Systemic inhibition can lead to adverse effects, including autoimmunity and impaired wound healing. The review concludes that future efforts must focus on:
Developing isoform-specific or cell-targeted inhibitors (e.g., using nanoparticle delivery systems) to minimize systemic toxicity.
Exploring combination therapies that target TGF-β alongside other fibrogenic pathways to enhance efficacy and overcome resistance.
Advancing the translation of TCM-derived compounds through rigorous preclinical and clinical studies to define their precise targets and pharmacokinetics.
In summary, this review provides a comprehensive overview of TGF-β as a master switch in liver fibrosis and underscores the considerable, though challenging, therapeutic potential of its inhibition. By integrating insights from molecular pathways, clinical trial data, and natural products, it charts a course for future research aimed at bringing effective, targeted anti-fibrotic treatments to patients.
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https://www.xiahepublishing.com/2310-8819/JCTH-2025-00029
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.
