Applications of Medicinal Plants and Their Metabolites in Fibrotic Disease: Novel Strategies, Mechanisms, and Their Impact on Clinical Practice

Houfu Qian^1,2Xiang Tao³Yuan Li⁴Xin Wang⁵Bing Yu^6*

• ¹Department of Gastroenterology, Taizhou Second People's Hospital, Jiangsu Province, China., Taizhou, China
• ²Department of Cell Biology, Naval Medical University, Shanghai, China., Shanghai, China
• ³Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China, Shanghai, China
• ⁴Department of Nephrology, Affiliated Hospital of Nantong University, Nantong, China, Nantong, China
• ⁵Molecular and Cellular Therapeutics, University of Minnesota Twin Cities, St. Paul, United States., Twin, United States
• ⁶Department of Cell Biology, Naval Medical University, Shanghai, China, Shanghai, China

Fibrotic diseases represent a major global health challenge, pathologically characterized by the excessive deposition of extracellular matrix, which ultimately leads to organ dysfunction and failure (Zhao et al., 2022;Kim et al., 2025b). Current therapeutic options remain severely limited, with only a few anti-fibrotic agents approved for clinical use, such as pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF) and the more recently approved resmetirom for non-alcoholic steatohepatitis (NASH)-related liver fibrosis (Ahangari et al., 2022;Harrison et al., 2024). However, the utility of these drugs is considerably constrained by issues including significant gastrointestinal side effects and poor patient tolerance, which markedly limit their clinical efficacy and long-term adherence. In response to these challenges, natural products derived from medicinal plants and fungi, with their innate "structural diversity -multi-components -multi-targets" synergy, excellent biocompatibility and safety profiles, have emerged as a highly promising new direction in the research on therapies for fibrotic diseases (Kuete et al., 2025;Li et al., 2025). This special issue assembles eight insightful contributions (table1) that collectively advance our understanding of the molecular mechanisms and therapeutic potential of natural compounds in diverse fibrotic contexts, spanning liver, lung, kidney, intestinal, and systemic fibrotic diseases. Each study highlights novel strategies and pathways, reinforcing the translational promise of medicinal plants and their metabolites in fibrosis management.The study by Min Yang et al. demonstrates that rhaponticin (RHA) alleviated liver fibrosis in a carbon tetrachloride-induced rat model by improving liver function, inhibiting the activation of hepatic stellate cells, and reducing collagen deposition. Nontargeted metabolomics revealed modulation of multiple metabolic pathways, particularly glycerophospholipid, phenylalanine, and tryptophan metabolism, suggesting a multi-targeted mechanism underlying RHA's therapeutic effects. These findings not only provide robust evidence supporting RHA as a promising natural product for anti-liver fibrosis therapy, but also deepen our understanding of the metabolic mechanisms underlying liver fibrosis, offering important insights for future research in this field.The review by Meiting Ma et al. offers a comprehensive and insightful overview of idiopathic pulmonary fibrosis (IPF), integrating key pathogenic mechanisms, such as epithelial injury, fibroblast-to-myofibroblast transition, ECM dysregulation, and key signaling cascades including TGF-β/Smad and NF-κB, with a systematic survey of over twenty anti-fibrotic natural products from terrestrial and marine sources. A particular strength lies in its organization of diverse natural compounds, including flavonoids, saponins, polyphenols, and marine alkaloids, according to their multi-target mechanisms, which helps clarify their therapeutic relevance. Notably, the authors do not shy away from addressing translational challenges such as bioavailability and mechanistic complexity, while also outlining how advanced tools like high-throughput screening and Artificial Intelligence (AI)-assisted drug design could accelerate future discovery. By bridging molecular pathogenesis, natural product pharmacology, and cutting-edge technology, this review offers a structured and forward-looking perspective that will be valuable for researchers exploring novel IPF therapeutics.The study by Zhili Xiong et al. offers valuable insights into the anti-fibrotic mechanism of Jingtian Granule (JT) in chronic kidney disease. Using an adenine-induced mouse model, the authors demonstrate that JT ameliorates renal fibrosis through activation of the mitochondrial deacetylase SIRT3, which deacetylates the tumor suppressor P53, thereby suppressing ferroptosis and lipid peroxidation. SIRT3 knockout abrogated JT's protective effects, confirming its pivotal role. In vitro experiments with HK-2 cells corroborated these findings via modulation of ROS and the SIRT3/P53/GPX4 axis. Importantly, this research bridges traditional Chinese medicine with modern cell death mechanisms, revealing a novel link between ferroptosis inhibition and renal anti-fibrotic therapy. The identification of the SIRT3/P53 axis not only elucidates a sophisticated molecular pathway but also highlights its potential as a therapeutic target for CKD treatment. It effectively elucidates the roles of inflammatory cells (eosinophils, mast cells, macrophages), profibrotic cytokines (IL-17, IL-6, IL-34), and gut microbiota metabolites in fibrosis progression. It also examines current and potential therapeutic agents including mesenchymal stem cells, PPAR-γ agonists, and pirfenidone, with emphasis on traditional Chinese medicine and its multi-target advantages. Furthermore, lifestyle interventions such as dietary modulation and vitamin D supplementation are proposed as adjunctive strategies, advocating integrative approaches to IBD-related fibrosis management. By bridging molecular mechanisms with holistic treatment approaches, this review makes a valuable contribution to the evolving paradigm of IBD-related fibrosis therapy.The study by Zhengju Zhang et al. presents a compelling investigation into the synergistic anti-fibrotic effects of polydatin and curcumin (PD+Cur) in a bleomycininduced model of connective tissue disease-associated interstitial lung disease (CTD-ILD). Using multi-omics approaches, the authors convincingly demonstrate that PD+Cur alleviates alveolar damage and fibrosis through activation of GABBR, leading to downstream suppression of the PI3K/AKT/TGF-β signaling axis. Further pharmacological validation using GABBR agonists and antagonists solidifies the mechanistic link between target engagement and therapeutic outcome. These findings not only reveal a novel role for GABBR in fibrotic lung disease but also highlight the promise of natural product combinations as multi-target strategies for treating CTD-ILD.The review by Shiqi Chen et al. provides an authoritative overview of pharmacological strategies for liver fibrosis, systematically cataloging interventions from conventional drugs, repurposed drugs, plant-derived metabolites, and traditional Chinese formulas. Notably, the authors highlight promising advanced approaches, such as combination therapies, extracellular vesicles, and nanotechnology, for enhancing targeting precision. While acknowledging encouraging preclinical and clinical results, the review also critically identifies persistent gaps, including the lack of standardized efficacy assessment and large-scale validation. By emphasizing the need for rigorous clinical trials and improved translational frameworks, this work constructively outlines a pathway to bridge the gap between natural product research and clinically applicable liver fibrosis therapies.The review by Jiarui Zhao et al. comprehensively analyze icariin (ICA) as a multi-organ anti-fibrotic agent, covering fibrosis in the lung, heart, kidney, liver, bladder, skin, and arachnoid membrane. The authors delineate ICA's pleiotropic mechanisms-ranging from anti-inflammatory and antioxidant effects to the regulation of mitochondrial function, cell death, autophagy, and macrophage polarization-through key pathways including TGF-β/Smad, NF-κB, AMPK, Nrf2/HO-1, and WNT/β-catenin. The authors not only present compelling preclinical evidence but also critically address pharmacokinetic limitations, highlighting advanced extraction methods and nanodelivery strategies to overcome bioavailability challenges. While the preclinical profile is notably robust, the review appropriately emphasizes the crucial need for clinical validation. This work successfully positions ICA as a promising multi-target natural product while constructively outlining the translational pathway from mechanistic understanding to potential clinical application.The study Hui Yin et al. presents a mechanistically insightful investigation into the antifibrotic properties of fangchinoline (FAN) in a diethylnitrosamine-induced liver fibrosis model. The authors demonstrate that FAN attenuated liver injury and collagen deposition by inhibiting stellate cell activation and extracellular matrix protein expression and reveal that FAN regulate taurine metabolism, specifically restoring CSAD enzyme expression and hepatic taurine levels. Taurine synergistically enhanced FAN's anti-fibrotic effect by reducing reactive oxygen species and activating the Nrf2 antioxidant pathway. Combined treatment with the ROS scavenger N-acetylcysteine further potentiated these effects. This study thus not only delineates a taurinemediated mechanism for FAN but also highlights the therapeutic potential of targeting metabolic pathways in liver fibrosis.Fibrosis, as a multifaceted pathological process driven by numerous factors and signaling cascades, inherently necessitates multi-target therapeutic strategies (Antar et al., 2023). The findings presented in this special issue strongly supports the role of medicinal plants and their bioactive metabolites as promising sources of such interventions. These natural agents demonstrate the ability to concurrently modulate key processes in fibrosis, including metabolic reprogramming, ferroptosis, immune responses, oxidative stress, and critical signaling pathways, thereby validating their potential for comprehensive therapeutic intervention. This multi-target capacity represents a distinct advantage over single-target agents, aligning more closely with the complex pathogenesis of fibrotic diseases.However, the current body of evidence remains largely confined to preclinical studies, characterized by limited sample sizes and a predominant reliance on in vitro and animal models. The critical absence of clinical trial data constitutes a major bottleneck for translation. Further complicating this transition are inherent challenges of natural products, such as suboptimal physicochemical properties (e.g., poor solubility, low bioavailability and short half-life), complex pharmacokinetics, and difficulties in standardization (Kim et al., 2025a;Liu et al., 2025a;Liu et al., 2025b).To bridge this gap, a convergent research paradigm is urgently needed. Future work should integrate traditional medical knowledge with advanced technological platforms-such as multi-omics, nanomedicine, and AI-to optimize drug delivery, validate mechanisms of action, and ultimately power rigorous clinical trials. We hope this special issue will inspire innovative approaches that bridge ethnopharmacology and modern science, ultimately advancing effective anti-fibrotic therapies into clinical practice. Hui Yin et al.