Aug 2026· Frontiers in Pharmacology· Vol 17· 0 citations· 134 references
Medicine
TL;DR
This PUF is considered as a potential integrative therapeutic approach for fibrosis-related diseases and for aggressive cancers with fibrosis, and is expected to target both tumour cells and the fibrotic tumour micro-environment, thereby integrating ethnopharmacological knowledge with molecular rationality.
Abstract
Fibrosis is a pathological condition characterised by excessive deposition of the extracellular matrix (ECM) and persistent activation of myofibroblasts, and is associated with many chronic diseases. The association between fibrosis and cancer is increasingly recognised, where fibrosis contributes to the progression of cancer by increasing metastatic potential and resistance to therapy, thereby leading to poor clinical outcomes. A novel Polyherbal Unani Formulation (PUF), based on the Unani system of medicine, possesses a distinct phytochemical constitution with wide-spectrum therapeutic properties. Phytochemicals such as chebulinic acid, picrosides, flavonoids, and phenolic derivatives are reported to exert multi-targeted effects by attenuating oxidative stress, suppressing pro-fibrotic signalling pathways (TGF-β/Smad, NF-κB, PI3K/Akt), inhibiting epithelial-mesenchymal transition (EMT), and restoring fibroblast-to-myofibroblast plasticity. These individual compounds were systematically evaluated preclinically, establishing their effectiveness in modulating key molecular targets. Challenges such as phytochemical standardisation, bioavailability, and clinical validation remain significant for this distinct drug formulation, thereby improving its translational value. This review article considers PUF as a potential integrative therapeutic approach for fibrosis-related diseases and for aggressive cancers with fibrosis. In summary, we expect this PUF to target both tumour cells and the fibrotic tumour micro-environment, thereby integrating ethnopharmacological knowledge with molecular rationality.
Fibrosis is the outcome of chronic diseases and manifests as an abnormal repair process in which normal parenchyma is progressively replaced by deposited extracellular matrix. It leads to organ dysfunction and is associated with high morbidity, disability, and mortality, thereby becoming a major public health concern. Traditional Chinese medicine shows multi-target, multi-pathway strategies with favorable safety profiles. Curcumin (CUR), a polyphenolic metabolite derived from Curcuma longa L. (Zingiberaceae), has been shown to modulate key fibrotic signaling pathways, including AMPK, autophagy, extracellular-regulated protein kinase (ERK), transforming growth factor β (TGF-β)/Smad, JNK, and Wnt/β-catenin. However, a critical analysis of more than 200 included studies reveals that the current evidence base is fundamentally descriptive rather than conclusive. The data show reproducible antifibrotic signals in acute chemical injury models (bleomycin (BLM), carbon tetrachloride (CCl4), and streptozotocin (STZ) when CUR is administered prophylactically. The data do not show (1) efficacy in chronic, progressive disease models that recapitulate human pathology; (2) a dose-response relationship linking achievable tissue concentrations to antifibrotic effects; (3) superiority over or an add-on benefit to standard-of-care antifibrotics; or (4) robust clinical efficacy beyond small, uncontrolled case series. Despite this promising preclinical evidence supporting CUR's antifibrotic efficacy, clinical translation remains constrained by several critical limitations. The majority of evidence derives from in vitro studies using supraphysiological concentrations that far exceed achievable human plasma levels and from animal models that incompletely recapitulate the chronic, progressive nature of human fibrotic diseases. Additionally, the inherently poor oral bioavailability of CUR-despite advances in formulation strategies-remains a persistent obstacle. A critical appraisal of the existing literature further reveals substantial heterogeneity in experimental designs, a predominance of positive results suggestive of publication bias, and insufficient mechanistic validation to establish causality. This review outlines the mechanisms of action, safety, adverse effects, drug interactions, and the application of CUR-related nanocomposite products, thereby providing a foundation for in-depth research on its antifibrotic properties and clinical application.
Ting Luo, Jia Gao, Qingzhi Liang et al.· Frontiers in Pharmacology· 0 citations
Background:Liver fibrosis is a progressive pathological process that is the super-accumulation of extracellular matrix (ECM) due to chronic liver damage. Dysregulated signaling pathways involving interleukin-6 (IL-6), epidermal growth factor receptor (EGFR), and protein kinase B (AKT1), are implicated in hepatic stellate cell (HSC) activation, fibrogenesis, and progression toward cirrhosis and hepatocellular carcinoma (HCC). Despite advances in understanding these mechanisms, effective pharmacological interventions with favorable safety profiles remain limited. Methods:The current research examined the effects of two naturally occurring flavonoids, Kaempferol and Coumestrol on fibrosis-linked oncogenic signaling using an integrated in silico and in vitro study. Molecular docking studies were conducted to assess the binding affinities and the interaction profiles of both compounds with IL-6, EGFR, AKT1, and Caspase-3 (CASP3). Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling was used to predict pharmacokinetic and toxicity properties to evaluate drug-likeness and safety parameters. In vitro experiments were conducted in HepG2 and Huh7 hepatocellular carcinoma cell lines to evaluate cytotoxicity, cell viability, migration, invasion, colony formation, and expression of IL-6, EGFR, AKT1, and Caspase-3. IC50 values were derived from dose-response curves generated from three independent technical experimental replicates.Results:Docking analysis showed stable binding interactions of both compounds at the active sites of IL-6, EGFR, AKT1, and CASP3, supported by hydrogen bonding and hydrophobic interactions, and ADMET predictions indicated favorable absorption with manageable toxicity profiles. In HepG2 and Huh7 cells, Kaempferol and Coumestrol showed dose-dependent reductions in cell viability, migration, invasion, and colony formation, along with downregulation of EGFR, AKT1, and IL-6 and upregulation of Caspase-3 at the transcript level. Conclusion: These findings suggest that Kaempferol and Coumestrol modulate IL-6/EGFR/AKT1-associated oncogenic signaling in hepatocellular carcinoma cells in vitro, indicating possible relevance to fibrosis-to-HCC progression. However, this study did not directly assess hepatic stellate cell activation or classical fibrogenic markers, and further studies using HSC models and in vivo validation are needed to confirm anti-fibrotic potential.
Unknown authors· International Journal of Pha...· 0 citations
Future directives necessitate rigorous botanical authentication, pharmacokinetic/pharmacodynamic profiling, and adoption of human-relevant models, such as induced pluripotent stem cell-derived cardiomyocytes, to bridge the bench-to-bedside gap.
Tian-Tian Long, Juncheng Ma, Wei-Jun Hu et al.· International Journal of Mol...· 0 citations
Oral submucous fibrosis (OSMF) is a chronic, progressive fibrotic disorder with significant malignant potential, and limited effective treatments due to an incomplete understanding of its underlying molecular mechanisms. This narrative review synthesizes current evidence on the key molecular networks involved in OSMF pathogenesis, highlighting the central role of the TGF-β1/Smad, CTGF, and COL1A1 pathways in maintaining fibroblast activation, supporting myofibroblast activity, and promoting pathological collagen accumulation. It also integrates recent findings on how profibrotic signaling interacts with important angiogenic and epithelial growth factors such as VEGF, FGF, and EGF, creating a stage-dependent fibrotic microenvironment. In early OSMF, increased angiogenic signaling, especially through the VEGF/PI3K–Akt pathway, helps maintain blood supply. However, as the disease progresses, TGF-β-induced pathways become dominant, leading to vascular rarefaction, tissue hypoxia, epithelial instability and worsening fibrosis that increases the risk of malignant transformation. By critically appraising molecular, cellular, and translational studies, this review identifies key pathways linking fibrosis, angiogenesis, and epithelial changes in OSMF. It suggests that stage-specific and combined targeting of TGF-β1, CTGF, COL1A1, along with angiogenic and epithelial pathways, may help reverse fibrosis, restore normal tissue perfusion, reduce cancer risk, and support the development of better therapies and biomarkers beyond symptom relief.
Samar Kamran, Nabeel Reza, Zurairah Berahim et al.· International Journal of Mol...· 0 citations
: Cancer and fibrosis are two pathological conditions that although of different clinical appearance have several shared characteristics, most likely because of a common etiology (for example in case of Silica). Here, we present a comprehensive review of the literature, with respect to Crystalline Silica, a known carcinogenic and fibrogenic agent, aiming to highlight common denominators between both diseases, as well as their differences. The results from various studies point to the involvement of the immune response, cancer-associated fibroblasts (CAFs), cellular communication and various signaling pathways, including Notch, Wnt/ β -catenin, and YAP/TAZ in their respective pathogenesis. In particular, pro-inflammatory cytokines are reported to trigger a stromal reaction mediated by adaptive immunity, leading to fibrosis. Conversely, an imbalance between the Treg and Teff cells alongside the activity of CAFs promotes cancer development. The Wnt/ β -catenin pathway appears to play a pivotal role in these divergent responses. We propose a working hypothesis based on the mechanisms of action of silica and its effect with the perspective of developing targeted therapies for silica-induced disease.
R. Zefferino, A. Carbone, Aglaja Zefferino et al.· European Cytokine Network· 0 citations
Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant fibroblast proliferation and excessive expression and deposition of extracellular matrix (ECM) by myofibroblasts, ultimately resulting in progressive and irreversible disorder or even loss of the pulmonary function. IPF is incurable with limited therapeutic options and low survival rate, thus the discovery of the therapeutic potential agents for IPF is in urgent need. Here, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9H-pyrido[3,4-b] indole-3-carboxylate (Z86) as a promising bioactive agent against Bleomycin (BLM) induced pulmonary fibrotic mice with the lung abnormalities including histological alteration, accumulation of ECM, as well as markers of EMT (epithelial-mesenchymal transition) were all relieved upon Z86 treatment in C57BL/6 mice. Consistent to the activity in vivo, Z86 decreased TGF-β induced cell migration, fibrotic marker expression, and myofibroblast activation in A549 and HFL1 cells. In further mechanism of action study of Z86 against IPF, we found TGF-β (transforming growth factor β) /Smad2/3 signaling pathway was substantially attenuated in TGF-β treated A549 and HFL1 cells, with remarkably decreased protein level of Smad2/3. Further, we identified Z86 as a novel USP15 inhibitor. Correspondingly, Z86 interacted with USP15, promoted the ubiquitination and degradation of Smad2/3 and disrupted TGF-β/Smad2/3 signaling pathway. Taken together, our findings demonstrated that Z86 suppressed TGF-β induced pulmonary fibrosis in A549 and HFL cells and BLM induced pulmonary fibrotic mice through inhibiting TGF-β/Smad2/3 signaling, and provided the possibility of USP15 inhibitors as the potential drug candidates for idiopathic pulmonary fibrosis. Z86 suppresses BLM induced pulmonary fibrosis in mice. Z86 reverses TGF-β induced EMT in pulmonary fibroblast cells. Z86 attenuates TGF-β caused ECM deposition in pulmonary fibroblast cells. Z86 induces remarkable post-transcriptional downregulation of Smad2/3. Z86 targets USP15 to promote the degradation of Smad2/3. Z86 suppresses BLM induced pulmonary fibrosis in mice. Z86 reverses TGF-β induced EMT in pulmonary fibroblast cells. Z86 attenuates TGF-β caused ECM deposition in pulmonary fibroblast cells. Z86 induces remarkable post-transcriptional downregulation of Smad2/3. Z86 targets USP15 to promote the degradation of Smad2/3.
Yu-yang Wang, Shao-hua Zhang, Rong Geng et al.· Natural Products and Biopros...· 0 citations
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