Aug 2026· International Journal of Molecular Sciences· Vol 27, pp. 7075· 0 citations· 133 references
Medicine
TL;DR
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.
Abstract
Myocardial fibrosis (MF) is a hallmark of pathological cardiac remodeling, driven by extracellular matrix (ECM) accumulation, fibroblast activation, and oxidative stress. Diverse natural products—notably alkaloids, flavonoids, terpenoids, and saponins—exhibit emerging antifibrotic potential. A comprehensive literature synthesis through July 2026 across PubMed, Web of Science, and Scopus categorized these agents by phytochemical class and disease models, delineating direct antifibrotic efficacy from indirect cardioprotection. Mechanistically, these compounds target TGF-β signaling, endothelial-to-mesenchymal transition (EndMT), autophagy/mitophagy, and ECM turnover. Robust preclinical evidence correlates with integrated histopathological assessment, specifically collagen and α-SMA quantification. However, translation remains impeded by model limitations, inadequate phytochemical standardization, and a critical paucity of clinical trials. Currently, no natural product holds clinical approval for MF. 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.
Abstract Renal fibrosis represents a shared pathological endpoint that drives the progression of chronic kidney disease (CKD) toward end-stage kidney disease (ESKD). Although current therapies can delay CKD progression, they have limited capacity to reverse established fibrotic remodeling, underscoring the need for mechanism-oriented anti-fibrotic interventions. Plant-derived preparations have long attracted attention because of their multi-component, multi-target, and multi-pathway pharmacological profiles. More recently, advances in separation, purification, and pharmacological evaluation have redirected research interest from crude extracts toward defined bioactive natural products. A growing body of evidence suggests that flavonoids, alkaloids, terpenoids, glycosides, polyphenols, quinones, and other natural products may exert anti-fibrotic effects by targeting key pathological processes, including inflammation, oxidative stress, mitochondrial dysfunction, metabolic reprogramming, autophagy dysregulation, epigenetic regulation, and regulated cell death. This review summarizes recent advances in the use of natural products for the treatment of renal fibrosis, with a particular focus on their underlying molecular mechanisms, current status of clinical translation, and the challenges that remain.
Yan Liu, Lei Gao, Hao Xu et al.· Renal Failure· 0 citations
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.
Rithika Thangaraju, N. Kamlesh, M. Shipin et al.· Frontiers in Pharmacology· 0 citations
This review examines emerging mechanisms that govern kidney fibrogenesis, with emphasis on therapeutic tractability, and considers how experimental models can improve target prioritization and drug development, and summarizes repurposed drugs, pathway-targeted agents, receptor-directed strategies and cell-based approaches under preclinical or clinical evaluation.
Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition and progressive myocardial remodeling, is a common pathological outcome of various cardiovascular diseases and lacks effective targeted anti-fibrotic therapies. Panax ginseng and its related preparations, including major ginsenosides (e.g., Rb1, Rg1, and Rg3), standardized extracts, and compound formulas, have garnered growing interest owing to their multi-component, multi-target pharmacological activities and integrative regulatory effects. This review systematically summarizes recent advances in the basic and clinical research of ginseng-based medicines in the prevention and treatment of cardiac fibrosis. Preclinical evidence demonstrates that ginseng and its active constituents attenuate key pathological processes, including oxidative stress, inflammatory responses, apoptosis, and autophagy dysregulation, primarily through modulation of signaling pathways such as TGF-β/Smad, NF-κB, and PI3K/Akt. These regulatory effects collectively contribute to the inhibition of fibroblast activation, reduction of collagen deposition, and improvement of myocardial structure and function. Emerging clinical studies further suggested potential benefits in improving cardiac function and modulating fibrosis-related biomarkers in patients with hypertension, coronary heart disease, and heart failure (HF). Despite these promising findings, several challenges hinder clinical translation, including low oral bioavailability, the mechanistic complexity of compound formulas, and insufficient high-quality clinical evidence. Future investigations should integrate novel drug delivery strategies, systems pharmacology approaches to elucidate holistic mechanisms, and well-designed randomized controlled trials to facilitate the development of ginseng-based medicines as potential therapeutic agents for cardiac fibrosis.
Meng Zhi, Ao Wang, Hailian Quan et al.· Chinese Herbal Medicines· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most prevalent chronic liver disease worldwide, yet no pharmacological therapy has achieved regulatory approval. Flavonoids, plant-derived polyphenols encompassing seven structural subclasses, exhibit considerable preclinical promise through multi-target mechanisms but face translational barriers owing to poor oral bioavailability and insufficient clinical validation. This review systematically evaluates 33 structurally characterized single flavonoids for their therapeutic mechanisms, pharmacological targets, and translational prospects in MASLD, integrating evidence from cellular models, diverse rodent models, and available clinical trials. A tiered evidence classification (Levels A–C) was applied based on clinical data availability, multi-model validation, mechanistic depth, and study design rigor. Mechanistically, flavonoids restore hepatic lipid homeostasis by concurrently inhibiting SREBP-1c-mediated de novo lipogenesis and promoting PPARα-driven fatty acid β-oxidation via AMPK activation; ameliorate insulin resistance through IRS-1/PI3K/Akt signaling; attenuate hepatic inflammation by suppressing NF-κB/NLRP3 inflammasome cascades; reinforce antioxidant defenses via Nrf2/ARE-mediated induction of HO-1, SOD, and GPX4 with concomitant ferroptosis inhibition; enhance autophagic-lysosomal lipid clearance through TFEB nuclear translocation and Sirt1-dependent lipophagy; and remodel gut microbiota composition to fortify intestinal barrier integrity. Genistein, dihydromyricetin, quercetin, and kaempferol exemplify polypharmacological engagement across multiple pathways. Despite robust mechanistic evidence, oral bioavailability remains limited to 1%–5% owing to poor aqueous solubility, extensive phase II conjugation, and food-matrix interactions. Emerging strategies—carbamate prodrugs, nanoliposomes, biomimetic nanoemulsions, and colon-targeted nanoparticles—demonstrate feasibility in surmounting these barriers. Clinical evidence reveals compound-specific efficacy profiles: hesperidin reduces steatosis and transaminases; genistein improves insulin sensitivity; naringenin ameliorates lipid profiles without altering fibrosis markers. Critical appraisal identifies persistent limitations including small sample sizes, predominant reliance on male animals, short intervention durations, and absence of biopsy-confirmed endpoints. Future research must prioritize rigorous multicenter randomized controlled trials with optimized formulations, comparative efficacy studies, systematic safety evaluations, and multi-omics integration to bridge the translational gap toward evidence-based flavonoid therapeutics for MASLD.
Zhonghai Dao, Jishen Li, Yiping Liu et al.· Frontiers in Pharmacology· 0 citations
Liver fibrosis is a progressive consequence of chronic hepatic injury characterized by sustained activation of hepatic stellate cells (HSCs) within a complex network of metabolic and inflammatory signaling. This review critically examines selected plant-derived metabolites associated with herbs used in Traditional Chinese Medicine (TCM), including salvianolic acid B, curcumin, berberine, resveratrol, puerarin, glycyrrhizin, tetrandrine, oroxylin A, and schisandrin B, for their potential roles in modulating immunometabolic pathways relevant to fibrogenesis. A structured search of PubMed and Web of Science identified mechanistic, preclinical, and clinical studies. Overall, these compounds were reported to influence key pathways implicated in liver fibrogenesis, including glycolysis, mitochondrial dysfunction, lipid metabolism, NF-κB, TGF-β/Smad, PI3K–Akt–mTOR, and HIF-1α signaling. However, the strength of evidence varies considerably across compounds. Curcumin and resveratrol have the most consistent translational data, whereas salvianolic acid B, tetrandrine, and oroxylin A remain supported primarily by preclinical findings with limited mechanistic and clinical validation. Current evidence is constrained by model heterogeneity, reliance on associative pathway analyses, and the scarcity of histologically confirmed clinical outcomes. These findings suggest that selected phytochemicals associated with TCM herbs may modulate immunometabolic processes involved in liver fibrosis, but their therapeutic potential remains incompletely defined and requires confirmation in standardized, mechanistically informed clinical studies.
Xiaoxin Liu, Yan-Xiu Li, Junke Guan et al.· Frontiers in Pharmacology· 0 citations