Volume 18,Issue 3,2026 Table of Contents

1 From empiricism to precision: SHINE strategy in anti-fibrotic drug discovery

Wen Huang a , ? , Zhaotong Cong b ,

2026, 18(3):491-493. DOI: https://doi.org/10.1016/j.chmed.2026.05.002

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2 Cardiometabolic reprogramming drives right ventricular dysfunction in pulmonary arterial hypertension: Novel mechanisms and therapeutic implications

Saihu Liu a , Mari Okazaki b , Yanling Wu a

2026, 18(3):494-498. DOI: https://doi.org/10.1016/j.chmed.2026.05.004

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With the understanding on right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH),the perspective innovatively integrates research paradigms on targeting cardiometabolic reprogramming of RV protective therapies to break through the bottleneck of current PAH treatment. The research focuses on three core areas: analyzing and validating metabolic dysregulation in the RV of PAH, exploring cell-specific metabolic dysregulation in the heart of PAH, and probing into the therapeutic strategy for PAH targeting RV metabolism. These aspects aim to deepen the scientific understanding of cardiometabolic reprogramming of RV dysfunction in PAH. This work provides a theoretical foundation and experimental evidence for developing RV-directed therapies that complement existing PAH treatments and improve patient outcomes.

3 Innovative strategies for anti-fibrotic drugs discovery from traditional Chinese medicine

Guang Xin a , Tao Wang a , Qilong Zhou a , Sanyin Zhang b , Zeliang Wei a , Ke Li a , Wei Chen b , Dan Sun b , Shilin Chen b , Zhaotong Cong b , ? , Wen Huang a , ?

2026, 18(3):499-514. DOI: https://doi.org/10.1016/j.chmed.2025.10.005

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Fibrotic diseases represent a major global health burden, with current therapies often limited by modest efficacy and substantial side effects. Traditional Chinese medicine (TCM) provides a rich yet underexplored reservoir for anti-fibrotic drug discovery, valued for its chemical diversity and extensive clinical history. Nonetheless, conventional approaches to deriving therapeutics from these multi-component formulas face significant challenges, including low tissue selectivity, limited target specificity, suboptimal scaffold optimization, and incomplete cross-scale validation. Here, we summarize recent advances in discovering TCM-derived anti-fibrotic compounds and highlight emerging strategies, including tissueoriented active compound discovery, fibrosis-target mining, scaffold optimization guided by targets and biosynthesis, and cross-scale validation. Building on these developments, we introduce the Smart Herbal-based Innovation and Translational Engine (SHINE), an intelligent discovery platform that prioritizes promising herbal candidates using modern computational and experimental methods; innovative development of optimized compounds or novel derivatives; a translational pipeline to unite preclinical findings and clinical validation; and a closed-loop feedback system where real-world evidence continuously informs drug repositioning and secondary development. SHINE bridges TCM principles with stateof-the-art drug discovery technologies, enabling the development of well-defined, mechanism-based small-molecule candidates from classical formulas. By integrating empirical herbal knowledge with advanced multi-omics, artificial intelligence, and biosynthetic engineering, SHINE aims to deliver firstin-class anti-fibrotic therapeutics with defined targets, improved safety, and demonstrable clinical efficacy.

4 Cardiometabolic reprogramming in pulmonary arterial hypertension:Implications for right ventricular dysfunction and therapeutic strategies

Guanghui Qian a , b , Peng Zhang a , b , Gaurav Choudhary a , b , Hongwei Yao a , b , c , ?

2026, 18(3):515-527. DOI: https://doi.org/10.1016/j.chmed.2026.04.004

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Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary arterial wall remodeling, right ventricular (RV) hypertrophy, and interstitial fibrosis, ultimately culminating in RV failure. The latter is the strong predictor of mortality in PAH. While current therapies primarily target the pulmonary vasculature and reduce RV afterload, they do not directly address the metabolic and structural maladaptation of the RV. Emerging evidence indicates that cardiometabolic reprogramming occurs in the RV of PAH patients, encompassing dysregulated glucose, lipid, and amino acid metabolism. These metabolic dysregulations are mirrored in preclinical models, where cardiomyocytes, endothelial cells, and fibroblasts exhibit reduced fatty acid oxidation, enhanced glycolysis, and altered mitochondrial function. Such alterations may promote cardiomyocyte lipotoxicity, impair contractile efficiency, disrupt endothelial barrier integrity, facilitate monocyte recruitment, and drive fibroblast proliferation and activation, collectively contributing to RV inflammation, fibrosis, and functional decline. Understanding these cellspecific metabolic reprogramming is critical, as they may represent both compensatory and pathogenic mechanisms during the progression from RV adaptation to maladaptation. This review provides a comprehensive overview of recent advances in elucidating metabolic dysregulation in the RV of PAH patients and relevant in vivo and in vitro models. The therapeutic potential of targeting these pathways using metabolic modulators, small molecules, and natural products is also discussed, with the goal of developing RV-directed therapies that complement existing PAH treatments and improve patient outcomes.

5 Systems pharmacology of traditional Chinese medicine in fibrosis: From multi-target mechanisms to translational validation

Ahmed I. Foudah , Aftab Alam ?

2026, 18(3):528-540. DOI: https://doi.org/10.1016/j.chmed.2026.05.008

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Systems biology research has integrated network pharmacology with clinical data to investigate traditional Chinese Medicine (TCM) antifibrotic mechanisms across multiple biological pathways. These combined approaches draw on chemical-protein interaction databases, transcriptomic and metabolomic profiling, protein–protein interaction networks, molecular docking, randomized trial and large cohort study evidence. Yinchenhao Decoction, Danggui Liuhuang Decoction, Curcumae Rhizoma (Ezhu in Chinese)-Astragali Radix (Huangqi in Chinese) herb pair, and Angelicae Sinensis Radix (Danggui in Chinese)-Chuanxiong Rhizoma (Chuanxiong in Chinese) herb pair regulate transforming growth factor-b (TGF-b)/mothers against decapentaplegic homolog (Smad), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), nuclear factor-jB (NF-jB), mitogen-activated protein kinase (MAPK), and janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways. Integration of these signals is associated with suppression of inflammation, altered regulation of apoptosis, modulation of cellular activation, and extracellular matrix remodeling in hepatic, cardiac, and pulmonary fibrosis models. This multi-layered framework offers a rational basis for hypothesis generation in drug repositioning and development of novel antifibrotic candidates, although clinical validation remains limited and further rigorous trials are warranted.

6 Combatting pulmonary fibrosis with Astragalus membranaceus: A review of active components and multifaceted mechanisms

Xiujuan Sun a , Jingwen Zhao a , Yiteng Ma a , Zhihao Kong a , Guangyue Su a , b , c , ?

2026, 18(3):541-554. DOI: https://doi.org/10.1016/j.chmed.2026.04.007

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Pulmonary fibrosis (PF) is a chronic progressive lung disease characterized by excessive deposition of extracellular matrix (ECM) and loss of lung function. Treatment options are limited and can only delay disease progression, making the development of novel therapeutic strategies crucial. Astragalus membranaceus (AM), a traditional Chinese medicinal herb renowned for its lung-tonifying and immunomodulatory properties, contains bioactive constituents such as flavonoids, saponins, and polysaccharides. These components exhibit anti-inflammatory, antioxidant, anti-fibrotic, and immunoregulatory activities, demonstrating therapeutic potential in PF. This review systematically elucidates the complex pathogenesis of PF, comprehensively summarizes the principal chemical constituents of AM, and highlights its multi-targeted anti-fibrotic mechanisms of action. Research demonstrates that AM and its bioactive constituents exert anti-fibrotic effects through multiple pharmacological actions: inhibiting fibroblast activation, reversing epithelial-mesenchymal transition (EMT), modulating immune-inflammatory responses, protecting alveolar epithelial cells (AECs), and ameliorating mitochondrial function. Through the synergistic interaction of its multiple components and multi-targeted effects, AM demonstrates significant advantages in combating PF. This review provides a comprehensive theoretical basis for deepening the understanding of AM anti-fibrotic mechanisms and offers practical guidance for developing novel anti- fibrotic agents based on traditional Chinese medicine and its bioactive constituents.

7 Challenges and opportunities for ginseng-based medicines in treating cardiac fibrosis from mechanistic insights to clinical translation

Mengtao Zhi a , Ao Wang b , Hailian Quan a , ? , Lan Hong a , ?

2026, 18(3):555-570. DOI: https://doi.org/10.1016/j.chmed.2026.05.014

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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-b/Smad, NF-jB, 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.

8 Piperine attenuates fibrogenesis and inflammation in hepatic fibrosis by switching STAT3 phosphorylation at Ser727

Xu Dai , Yunuo Wu , Lihua Lian , Zhenyu Cui , Jixing Nan , Yanling Wu ?

2026, 18(3):571-584. DOI: https://doi.org/10.1016/j.chmed.2026.05.007

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Objective: Piper nigrum is a medicinal and edible spice that is popular worldwide due to its unique spicy flavor, and is considered as a folk medicine for treating digestive system diseases. Piperine (PIP) is a bioactive alkaloid derived from P. nigrum, with remarkable hepatoprotective efficacy. Hepatic fibrosis represents a critical phase in the advancement of distinct chronic liver conditions towards cirrhosis, and currently lacks effective therapeutic drugs. The study aims to investigate the hepatoprotective functions of PIP and the underlying mechanism of PIP in combating hepatic fibrosis. Methods: C57BL/6J mice with hepatic fibrosis were induced by thioacetamide (TAA) and subsequently subjected to treatment with PIP or curcumin. Immortalized rat hepatic stellate cells (HSCs) were stimulated with transforming growth factor-b (TGF-b), followed by culture with PIP or niclosamide [signal transducer and activator of transcription 3 (STAT3) inhibitor], respectively. Human hepatic stellate cell line LX-2 were activated by TGF-b and transfected with specific small interfering RNA (siRNA) to silence STAT3 gene, and afterwards cultured with PIP. The mouse AML-12 cells and macrophage-like murine cells Raw 264.7 were stimulated with lipopolysaccharide (LPS), followed by culture with PIP. Results: In vivo, PIP reduced serum transaminase levels, collagen deposition, and decreased the excessive accumulation of extracellular matrix (ECM), comprising a-smooth muscle actin (a-SMA), collagen type I (Collagen I), and tissue inhibitor of metalloproteinases-1 (TIMP-1)/matrix metalloproteinase 13 (MMP13) ratio expressions. PIP inhibited inflammatory cytokines release and myeloperoxidase (MPO) expression, including interleukin-1 receptor type 1 (IL-1R1), cysteine-aspartic acid protease-1 (Caspase-1), and IL-6. PIP specifically inhibited STAT3 phosphorylation at Ser727, downregulated phosphorylated janus kinase 2 (p-JAK2), and upregulated suppressor of cytokine signaling 3 (SOCS3) and protein inhibitor of activated STAT 1/3 (PIAS1/3) expressions. In vitro, PIP inhibited ECM deposition and inflammatory cytokines release in activated HSCs. PIP selectively suppressed p-STAT3 at Ser727 without affecting Tyr705, and modulated p-JAK2, SOCS3, and PIAS1/3 expressions in activated HSCs, function as a STAT3 inhibitor. PIP inhibited LPS induced M1 polarization of RAW 264.7 macrophages. PIP decreased Cleaved Caspase 3 expression and apoptotic cells in LPS induced AML 12 hepatocytes. STAT3 deficiency amplified regulation of PIP on a-SMA and p-JAK2, as well as its upregulation on SOCS3 and PIAS1/3 in activated LX-2 cells. Conclusion: PIP improved hepatic fibrosis via inhibiting ECM excessive deposition and inflammatory secretion. Switching STAT3 phosphorylation at Ser727 might be the underlying targets for PIP against hepatic fibrosis, which provide an effective candidate and therapeutical strategy for hepatic fibrosis.Objective: Piper nigrum is a medicinal and edible spice that is popular worldwide due to its unique spicy flavor, and is considered as a folk medicine for treating digestive system diseases. Piperine (PIP) is a bioactive alkaloid derived from P. nigrum, with remarkable hepatoprotective efficacy. Hepatic fibrosis represents a critical phase in the advancement of distinct chronic liver conditions towards cirrhosis, and currently lacks effective therapeutic drugs. The study aims to investigate the hepatoprotective functions of PIP and the underlying mechanism of PIP in combating hepatic fibrosis. Methods: C57BL/6J mice with hepatic fibrosis were induced by thioacetamide (TAA) and subsequently subjected to treatment with PIP or curcumin. Immortalized rat hepatic stellate cells (HSCs) were stimulated with transforming growth factor-b (TGF-b), followed by culture with PIP or niclosamide [signal transducer and activator of transcription 3 (STAT3) inhibitor], respectively. Human hepatic stellate cell line LX-2 were activated by TGF-b and transfected with specific small interfering RNA (siRNA) to silence STAT3 gene, and afterwards cultured with PIP. The mouse AML-12 cells and macrophage-like murine cells Raw 264.7 were stimulated with lipopolysaccharide (LPS), followed by culture with PIP. Results: In vivo, PIP reduced serum transaminase levels, collagen deposition, and decreased the excessive accumulation of extracellular matrix (ECM), comprising a-smooth muscle actin (a-SMA), collagen type I (Collagen I), and tissue inhibitor of metalloproteinases-1 (TIMP-1)/matrix metalloproteinase 13 (MMP13) ratio expressions. PIP inhibited inflammatory cytokines release and myeloperoxidase (MPO) expression, including interleukin-1 receptor type 1 (IL-1R1), cysteine-aspartic acid protease-1 (Caspase-1), and IL-6. PIP specifically inhibited STAT3 phosphorylation at Ser727, downregulated phosphorylated janus kinase 2 (p-JAK2), and upregulated suppressor of cytokine signaling 3 (SOCS3) and protein inhibitor of activated STAT 1/3 (PIAS1/3) expressions. In vitro, PIP inhibited ECM deposition and inflammatory cytokines release in activated HSCs. PIP selectively suppressed p-STAT3 at Ser727 without affecting Tyr705, and modulated p-JAK2, SOCS3, and PIAS1/3 expressions in activated HSCs, function as a STAT3 inhibitor. PIP inhibited LPS induced M1 polarization of RAW 264.7 macrophages. PIP decreased Cleaved Caspase 3 expression and apoptotic cells in LPS induced AML 12 hepatocytes. STAT3 deficiency amplified regulation of PIP on a-SMA and p-JAK2, as well as its upregulation on SOCS3 and PIAS1/3 in activated LX-2 cells. Conclusion: PIP improved hepatic fibrosis via inhibiting ECM excessive deposition and inflammatory secretion. Switching STAT3 phosphorylation at Ser727 might be the underlying targets for PIP against hepatic fibrosis, which provide an effective candidate and therapeutical strategy for hepatic fibrosis.

9 6-Gingerol alleviates hepatic fibrosis via inhibiting glycolytic reprogramming by targeting IGF2BP2

Hui Fang b , Fan Yang c , Min Shu d , Congjian Shi e , Qingxu Ha a , Junfa Yang f , Xiaodi Jia e , Yuansong Sun f , Zhenhua Ren b , Jian Gao a , ?

2026, 18(3):585-603. DOI: https://doi.org/10.1016/j.chmed.2026.05.012

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Objective: Hepatic fibrosis remains a major global health burden, often progressing to cirrhosis and hepatocellular carcinoma. Despite extensive research, no effective antifibrotic drugs are clinically approved due to the complexity of hepatic stellate cells (HSCs) activation and metabolic remodeling. Enhanced glycolysis is increasingly recognized as a metabolic hallmark sustaining the profibrotic phenotype of HSCs, representing a key but underexplored therapeutic target. This study explored the antifibrotic effect of 6- gingerol, the principal bioactive compound of Zingiber officinale, and revealed its novel mechanism involving metabolic-epitranscriptomic regulation of HSC activation. Methods: Liver fibrosis was induced in C57BL/6 mice by carbon tetrachloride (CCl4) and bile duct ligation (BDL), followed by oral 6-gingerol treatment. Complementary in vitro studies were performed in transforming growth factor-b1 (TGF-b1)-stimulated Lieming Xu-2 (LX-2 cells, a human hepatic stellate cell line) and primary HSCs from liver fibrosis mice. Integrated transcriptomics, network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) were combined with functional genetic manipulation to identify and verify molecular targets. Results: 6-Gingerol alleviated hepatic injury and collagen deposition in both CCl4- and BDL-induced models and improved liver function. Mechanistically, 6-gingerol inhibited glycolysis by downregulating hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), normalizing pyruvate and lactate metabolism, and restoring mitochondrial respiration. Insulin-like growth factor 2 mRNAbinding protein 2 (IGF2BP2) was identified as an important mediator associated with glycolytic enzyme expression and HSCs activation, and its silencing abolished 6-gingerol’s antifibrotic effects. Conclusion: Our study demonstrates that 6-gingerol attenuates hepatic fibrosis by targeting IGF2BP2- dependent glycolytic reprogramming, thereby restoring metabolic homeostasis and inhibiting HSCs activation. These findings uncover a novel metabolic-epitranscriptomic mechanism and suggest that 6- gingerol represents a promising therapeutic strategy for chronic liver diseases.

10 Formononetin alleviates ovarian fibrosis and inflammation via targeting SOCS3 and inhibiting TGF-b1/Smad signaling in PCOS

Aifen Liu a , Jingyan Hu a , Weili Yu a , Chuanyu Cang a , Chuanjing Shi a , Xi Wang a , Rui Wang a , Xuanwei Cai a , Fengbo Zhao a , Lei Zhang a , b , ?

2026, 18(3):604-620. DOI: https://doi.org/10.1016/j.chmed.2026.05.011

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Objective: Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by ovulatory dysfunction. Formononetin (FMN), a bioactive compound derived from leguminous plants, including Glycyrrhiza uralensis, Trifolium pratense, and Astragalus membranaceus, exhibits antiinflammatory and anti-fibrotic properties. This study aimed to evaluate the therapeutic effects of FMN in a PCOS rat model and elucidate its underlying molecular mechanisms. Methods: A PCOS-like model was established in 3-week-old female Sprague-Dawley rats by daily dehydroepiandrosterone (DHEA) injections. The efficacy of FMN was assessed by monitoring estrous cycles, hormone levels, glucose tolerance, and ovarian tissue morphology. Network pharmacology and transcriptome sequencing were used to predict the molecular targets and signaling pathways of FMN. The binding and stabilizing effects of FMN on suppressor of cytokine signaling 3 (SOCS3) were confirmed using molecular docking, molecular dynamics (MD) simulations, and cellular thermal shift assay (CETSA)-Western blotting (WB) (CETSA-WB). The expression of SOCS3, inflammation- and fibrosis-related markers, and the components of the transforming growth factor beta1 (TGF-b1)/Smad pathway were quantified by quantitative polymerase chain reaction (qPCR), WB, and immunohistochemistry. Functional validation was performed using SOCS3 small interfering RNA (siRNA). Results: DHEA successfully induced a PCOS-like phenotype, including disrupted estrous cycle, hyperandrogenism, an elevated luteinizing hormone to follicular stimulating hormone (LH/FSH) ratio, insulin resistance, and abnormal ovarian morphology. FMN treatment significantly reversed these abnormalities and reduced ovarian collagen deposition. Network pharmacology and transcriptome analyses indicated that the therapeutic efficacy of FMN was primarily attributable to its anti-fibrotic and antiinflammatory properties, with SOCS3 identified as a potential key molecule. Molecular docking and MD simulations, along with CETSA-WB, further revealed that FMN directly binds to SOCS3, enhancing its stability and thereby inhibiting ovarian fibrosis in PCOS. Moreover, qPCR, WB, and immunohistochemistry confirmed that FMN regulates the TGF-b1/Smad signaling pathway. Importantly, SOCS3siRNA abolished fibrotic-related collagen levels and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expression, supporting the notion that FMN ameliorates PCOS-induced ovarian fibrosis via SOCS3. Conclusion: FMN alleviated ovarian dysfunction and hyperandrogenism in DHEA-induced PCOS rats by stabilizing SOCS3 and inhibiting TGF-b1/Smad signaling, thereby attenuating ovarian fibrosis and inflammation. This reveals a novel SOCS3-centered mechanism for FMN and underscores its therapeutic potential for PCOS.

11 Huashi Baidu formula may attenuate adriamycin-induced myocardial injury via modulating NRF2-ATF3-SRXN1 axis-mediated ferroptosis

Weijie Li a , Xiang Li a , Congying Huang a , Yudong Liu a , Zhaochen Ma a , Zhaoyin Zhou b , c , Qiuyan Guo a , Congmin Xia d , Chao Wang a , Yute Zhong a , Ping Wang a , Haiyu Xu a , e , ?

2026, 18(3):621-634. DOI: https://doi.org/10.1016/j.chmed.2026.05.009

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Objective: Myocardial injury is a fatal adverse effect of adriamycin (ADR), which greatly limits its clinicalapplication. Numerous studies have shown that Huashi Baidu formula (HBF) may exert a satisfactoryeffect on myocardial function repair. This study aims to reveal the underlying mechanisms and mainbioactive compounds (BACs) of HBF against myocardial injury. Methods: Firstly, this study established an ADR-induced mouse model to assess the protective effects ofHBF against myocardial injury. Subsequently, transcriptomic profiling was conducted to screen the differentially expressed genes among the HBF treatment, ADR-induced model, and normal control groups.Following the construction and analysis of protein–protein interactions, gene set enrichment analysis,and co-expression matrix, the key targets of HBF against myocardial injury were screened and further validated based on the ADR-induced mouse model. An integrative approach combining network mapping,molecular docking, and molecular dynamics simulation was performed to identify the representative BACs. Results: Based on an ADR-induced myocardial injury mouse model, HBF significantly ameliorated myocardial injury by improving body weight loss, decreasing mortality, and rescuing severe cardiac fibrosis. A totalof 361 ADR-related genes and 42 HBF therapeutic effect-related genes were identified with the thresholdsP < 0.05 and fold change (FC) > 1.2 or < 0.833. Transcriptomic profiling-based networks demonstrated thatthe nuclear factor erythroid 2-related factor 2 (NRF2)-cyclic AMP-dependent transcription factor ATF-3(ATF3)-sulfiredoxin-1 (SRXN1) axis-mediated ferroptosis was the key target of HBF against myocardialinjury. In vivo validation showed that HBF treatment effectively inhibited serum enzymatic biomarkers ofgeneral myocardial injury (aspartate aminotransferase, lactate dehydrogenase, and creatine kinase), myofi- broblast activity (transforming growth factor beta 1 and a-smooth muscle actin), inflammatory cytokines(tumor necrosis factor-a and interleukin-6), oxidative damage (superoxide dismutase, malondialdehyde,accumulated iron content, and TUNEL-positive cells). Mechanically, HBF may restore the dysregulation ofthe NRF2-ATF3-SRXN1 signal axis, leading to inhibition of ferroptosis-associated protein expression.Emodin, rhein, and lactiflorin were identified as the underlying representative BACs of HBF against myocardial injury due to the strong binding affinities between candidate BACs and key targets [Kelch-like ECHassociated protein 1 (KEAP1), ATF3, SRXN1, system Xc- (SLC3A2/SLC7A11), glutathione peroxidase 4(GPX4), ferroportin (FPN), glutathione synthetase (GSS)]. Molecular dynamics simulations further verifiedthese findings, revealing the stable binding among the three components and the key targets. Conclusion: HBF may attenuate ADR-induced myocardial injury via modulating NRF2-ATF3-SRXN1 axismediated ferroptosis, and emodin, rhein, and lactiflorin are potential representative BACs.

12 Tanshinone IIA alleviates isoproterenol-induced myocardial injury via NR4A1/GATA4 pathway-mediated suppression of EndMT and oxidative stress

Guanfeng Xu a , b , Hang Wu a , b , Jie Zhang b , Yaxuan Wang a , b , Chongyu Shao a , b , Jiehong Yang a , b , Jin Han b , Haitong Wan a , b , c , ?

2026, 18(3):635-637. DOI: https://doi.org/10.1016/j.chmed.2026.05.006

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13 Multi-pathway targeting by natural products in chronic respiratory diseases: Opportunities, challenges, and future perspectives

Siqi Lin a , b , Lili Li c , Shiqing Zhuo a , b , Liang Yu a , b , Yu Huang a , b , Xiaofei Chen d , ? , Huihui Ti a , b , e , ?

2026, 18(3):638-642. DOI: https://doi.org/10.1016/j.chmed.2026.05.003

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Chronic respiratory diseases (CRDs) are multifactorial disorders driven by dysregulated inflammation,oxidative stress, and tissue remodeling. Conventional single-target therapies are insufficient to halt disease progression, underscoring the demand for alternative therapeutic approaches. Natural products,including bioactive compounds, herbal extracts, and traditional Chinese medicine (TCM) formulas, arecharacterized by their inherent multi-target properties and represent a promising intervention strategyfor CRDs. This perspective emphasizes natural products as network modulators that can simultaneouslyregulate multiple signaling pathways. The integration of systems biology, network pharmacology, andartificial intelligence (AI) is crucial for deciphering their polypharmacological mechanisms. The clinicaltranslation of natural products is anticipated to benefit from the implementation of several key strategies,including multi-omics integration, AI, targeted delivery, and blockchain-based quality control. By shiftingfrom a reductionist to a network-centric view, natural products can fulfill their potential as nextgeneration therapeutics for CRDs.

14 Puerarin as a multifaceted anticancer agent: Mechanisms, targets, and therapeutic potential across multiple cancers

Aida Alizamir a , Masoud Khanaghaei b , Farshad Mirzavi c , Ali Nokhodchi d , Laleh Ghavami e , Bita Taghizadeh f , ?

2026, 18(3):643-661. DOI: https://doi.org/10.1016/j.chmed.2025.11.001

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Puerarin (Pue), a key isoflavone from Pueraria lobata, has been traditionally used in Chinese medicine forcardiovascular, cerebrovascular, neurodegenerative, metabolic, and hepatic diseases. Recent studies indicate its anticancer potential across various malignancies. This review explores the current literature onPue’s anticancer activities, mechanisms of action, and molecular targets. Preclinical in vitro and in vivostudies suggest Pue’s effectiveness; however, challenges including standardization, selectivity, safety,and delivery hinder clinical translation. Specifically, dose optimization and rigorous standardizationare needed to fully elucidate Pue’s mechanisms, particularly in hormone-dependent cancers. The development of advanced drug delivery systems, such as nanosuspensions, nanoemulsions, and nanoparticles,is essential to improve Pue’s poor water solubility and stability, and to enhance targeted delivery. Studieshave shown that Pue can inhibit cancer cell proliferation, induce apoptosis, and suppress metastasis invarious cancer cell lines, including breast, colon, lung, and ovarian cancers. Pue’s anticancer mechanismsinvolve modulating multiple signaling pathways, including nuclear factor-jB (NF-jB), extracellular signal-regulated kinase (ERK), Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3), and Wnt signaling (Wnt), and targeting key molecules such as Caspases, Bcl-2-associated X protein (BAX), B-cell lymphoma-2 (BCL-2), matrix metalloproteinases (MMPs), and dual-specificity phosphatase 1 (DUSP1). Pue has also been found to enhance the efficacy of conventional chemotherapeuticagents such as cisplatin and oxaliplatin, and to overcome drug resistance. Overall, Pue shows promise as a multifaceted anticancer agent, which merits further investigation. This review provides a comprehensive overview of Pue’s anticancer effects, emphasizing its potential to guide future cancer treatment strategies.

15 Plantago mechanisms for enhanced wound healing: A review on bioactive phytoconstituents

Triana Hertiani a , ? , Muhammad Khafi b , Latifa Amalia b , c , Muhamad Bayu Irawan b

2026, 18(3):662-683. DOI: https://doi.org/10.1016/j.chmed.2026.05.015

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Plantago (Plantaginaceae family) exhibits remarkable diversity with over 200 species. These plants areclosely associated with traditional medicine worldwide, particularly as a wound healing therapy.Recent research has revealed phytoconstituents in various Plantago species, including flavonoids, alkaloids, terpenoids, phenolic acid derivatives, iridoid glycosides, fatty acids, and polysaccharides. Despitethe advanced ongoing research on Plantago extracts, there is still a gap in the evaluation of their potentialas an effective topical product for chronic wounds and in the way phytoconstituents contribute to theoverall effect in a single comprehensive systematic review. Therefore, this review aims to explore thewound healing capabilities of Plantago and its phytoconstituents, as well as elucidate their mechanismsof action. Our analysis emphasizes the significant wound healing potential in 25 Plantago species, notablyPlantago major, Plantago lanceolata, Plantago australis, Plantago asiatica, and Plantago ovata. These plantspecies contain a diverse array of 57 phytoconstituents that collectively contribute to these activities. In conclusion, this review confirms the huge potential of Plantago genus as a topical wound healing agent.The healing mechanisms cover a wide array of effects such as anti-bacterial activity, anti-apoptosis, stimulation of collagen synthesis and deposition, promotion of angiogenesis, suppression of inflammatory response, inhibition of cyclooxygenase, inhibition of MAPKs phosphorylation, and enhancement of endogenous antioxidant enzyme activity. A study on the network pharmacology of such potential is worth investigating as further research.

16 Chemical components and pharmacological action for Helianthus tuberosus and predictive analysis on its Q-markers

Xiaofei Wang a , Shu Zhong a , Li Wang b , Xu Xu b , c , ?

2026, 18(3):684-700. DOI: https://doi.org/10.1016/j.chmed.2025.04.003

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Helianthus tuberosus is a perennial herb that belongs to the Asteraceae family and Helianthus genus. It is cultivated in numerous northern and southern China regions, displaying numerous benefits such as its drought and frost resistance, ability to grow on most soils, and low fertilizer requirements. H. tuberosus contains various components, such as inulin, phenolic acids, terpenoids, flavonoids, steroids, phenylpropanoids, and other bioactive compounds with antioxidant, anti-inflammatory, antibacterial, antitumor, and immune-modulatory effects. In this paper, based on the new concept of quality marker (Qmarker) proposed by Academician Changxiao Liu, this study analyzed the relationship between plant affinity, chemical composition specificity, traditional medicinal properties, and chemical composition measurability of H. tuberosus, and predicted its Q-markers to provide a reference for the establishment of the quality evaluation system and comprehensive utilization of this herb.

17 A cross-cultural ethnobotanical assembly highlights diverse health-promoting functions of genus Panax globally

Ruyu Yao a , ? , Guomao Wu a , b , Michael Heinrich c , Angkhana Inta a , d , Ripu Kunwar e , Shengji Pei a , Yuhua Wang a , ?

2026, 18(3):701-712. DOI: https://doi.org/10.1016/j.chmed.2026.05.013

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Objective: This study aims to achieve a cross-cultural consolidation of the local and traditional knowledge in order to contribute to an understanding of these knowledge systems and to guide bioprospecting on Panax spp. Methods: Documentation-based taxonomic revision was performed to define the current accepted spe-cies in Panax. Historic uses of Panax spp. used in China was compiled using historical herbal literature. A cross-cultural ethnobotanical assembly was performed to compile the traditional uses of Panax spp. globally. With a network-based integration, the scattered local and traditional knowledge was consoli-dated and evaluated. Results: Currently, the genus Panax comprises 14 accepted species, mainly distributed in East Asia and eastern North America, all of which are used locally as traditional food and/or medicine. Four species are recorded in Chinese historical herbals. Eight species and one variety are used by 25 of the Chinese ethnic minorities. Beyond China, there are ten species and two varieties used traditionally in 12 countries. General health promotion functions are frequently mentioned. Conclusion: In different biocultural backgrounds, the used species and usages varied greatly, and even the same species can be used differently. For the first time, this study archives a comprehensive understanding on the health benefits of global Panax spp. and provides solid evidence for their versatility in main-taining human health from the perspective of ethnobotany.

18 Amentoflavone: A safe and novel penetration enhancer for transdermal applications

Yunhao Ren a , b , Fengyuan Song a , Haobin Wang a , Lihua Peng a , b , ?

2026, 18(3):713-724. DOI: https://doi.org/10.1016/j.chmed.2025.10.002

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Objective: Most of existing chemical penetration enhancers are along with obvious toxicity and skin irritation, new penetration enhancer is still to be developed yet. Amentoflavone is a flavonoid compound extracted from plant Selaginella tamariscina with high biocompatibility. However, its efficacy of penetration enhancers has not been studied. Methods: For the first time, the influence of amentoflavone to the skin penetration of caffeine was investigated by the Franz diffusion cells. The interactions of amentoflavone with the skin lipid and keratin were determined to identify the underlying mechanisms by the Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), etc. Results: Results showed that the penetration enhancement ratio (ER) of amentoflavone to model compound caffeine is nearly three times. The major mechanism was identified to be contributed to that, amentoflavone can not only change the keratin structure in stratum corneum (SC), but also undergo hydration interactions with intradermal components, therefore dissolving the lipid, loosening and reducing the barrier function of SC. Conclusion: These results give new evidence to the potential of amentoflavone as the novel effective chemical enhancer for the skin meditated delivery of external molecules, and it can exert the dual effects of traditional Chinese medicine activity and penetration enhancement.

19 Compatibility mechanism of Chrysanthemi Indici Flos compound against hepatocellular carcinoma based on balance of DNMTs/TET2

Zehui He , Cancan Guo , Fangping Zhang , Feifan Li , Yu Zhou , Leyi Ma , Xiaohui Wang , Yuefeng Bi ?

2026, 18(3):725-736. DOI: https://doi.org/10.1016/j.chmed.2026.03.003

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Objective: At present, traditional Chinese medicine (TCM) compounds is widely used in tumor therapy. However, due to the current single and simplistic efficacy evaluation indicators that are detached from the guidance of TCM theory, the elucidation of its mechanisms of efficacy is hindered. Therefore, the compatibility mechanism of Chrysanthemi Indici Flos compound (YJHFF) against hepatocellular carcinoma based on DNA methyltransferases/DNA demethylase ten-eleven translocation 2 (DNMTs/TET2) balanced relationship was explored according to the concept of the overall balance of TCM. Methods: This study screened the best compound compatibility ratio in the in vitro experiments, cell viability and DNMTs/TET2 balance were used as evaluation indicators to investigate the effects of single herb and different compatibility of compound on HepG2 and H22 cells. In vivo experiments were conduct on H22 liver orthotopic transplantation model mice. After treatment, the tumor tissues were observed by hematoxylin-eosin (HE), TUNEL and Ki67 immunohistochemical staining, respectively. The oxidative stress and liver function indicators in serum were detected by enzyme-linked immunosorbent assay. In addition, the proportion of tumor-infiltrating lymphocytes was detected by immunofluorescence staining. The mRNA expression levels of DNMTs and TET2 in tumor tissues were detected by RT-PCR. Results: The results of in vitro experiments showed that the cell proliferation inhibition rate was highly consistent with the change trend of DNMTs/TET2 balance, accordingly, this study obtained the optimal formula YJHFF. In the in vivo experiments, the tumor growth inhibition rate of YJHFF in 5 g/kg was 62.97%. Extensive necrosis, increased apoptosis and inhibited proliferation activity were observed in tumor tissue. Furthermore, the serum SOD activity was significantly increased, MDA, ALT, AST and AFP levels were significantly decreased, suggesting YJHFF could systematically alleviated oxidative stress and improved liver function. Besides, the infiltration of CD3+ , CD4+ and CD8+ T lymphocytes increased significantly, indicating that the body’s anti-tumor immune response was enhanced. Finally, RT-PCR analysis confirmed that antitumor effects were closely related to the core mechanism of DNMTs/TET2 expression regulation and reconstruction of epigenetic balance. Conclusion: This work confirmed the rationality and feasibility of the DNMTs/TET2 balance relationship as an evaluation indicator for the study of the compatibility mechanism of TCM compounds. The YJHFF screened under the guidance of DNMTs/TET2 balance has liver protection and tumor immune function, showing good anti-hepatocellular carcinoma effect.

20 Protective effect and mechanism of extracts of fruit of Taxus chinensis on hippocampus of chronic unpredictable mild stress rats

Shunling Zhang a , Jiayi Zhang a , Fei Zhang b , Maoyuan Ni a , Linwei Zhong b , Meimei Chen b , Zhaoyang Yang b , Huangwei Lei b , ?

2026, 18(3):737-745. DOI: https://doi.org/10.1016/j.chmed.2025.02.008

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Objective: The ambitious research aimed to explore the protective impact and mechanism of the ethyl acetate extract of Taxus chinensis fruits (TCFE) on the hippocampi of rats subjected to chronic unpredictable mild stress (CUMS). Methods: A total of 32 SD rats were randomly allocated into the control group, model group, TCFE group receiving 200 mg/(kg d) of TCFE, fluoxetine group receiving 2 mg/(kg d) of fluoxetine. The rats were induced with chronic unpredictable mild stress (CUMS) for 28 d, and concurrently administered the allocated drugs via gavage for the same duration. The body mass, performance in the open field test (OFT), and sugar-water preference rate of the rats in each group were assessed. The morphology of rat hippocampal tissues was examined using Hematoxylin-Eosin (HE) staining. Nissl staining was employed to observe hippocampal pathological changes, while ELISA was utilized to measure the levels of IL-1b, TNF-a, IL-6, and IL-18 in the hippocampus. Immunofluorescence was employed to identify the expression of the microglia (MG) marker Iba1 in the rat hippocampus. Furthermore, immunohistochemistry was utilized to detect the expression of Bax and Bcl-2 in the hippocampus. Real-time fluorescence quantitative PCR (qRT-PCR) was utilized to assess the expression levels of two apoptosis-related genes in the rat hippocampus. TUNEL assay was performed to detect tissue cell apoptosis in the rat hippocampus. Finally, Western blotting analysis was conducted to determine the expression of Bax and Bcl-2 proteins in the hippocampus. Results: The consumption of TCFE significantly enhanced body weight (P < 0.05), sucrose preference rate (P < 0.05), and total movement distance in the open field test (P < 0.05). It also improved hippocampal neuronal structure integrity and attenuated loss. Moreover, TCFE regulated the excessive activation of hippocampal microglia in rats, inhibited the expression of IL-1b and TNF-a (P < 0.05), and modulated the Bax and Bcl-2 expression levels, leading to a significant alteration in the Bax/Bcl-2 ratio (P < 0.05). Conclusion: TCFE shows promise in attenuating cell apoptosis through the modulation of the Bax/Bcl-2 ratio, suggesting a prospective approach for combating depression.

21 Modern scientific connotation of a traditional Chinese medicine theory: Rice vinegar extract of Artemisia argyi exhibits excellent antifungal effects against dermatophytes

Le Chen a , c , Wenli Xu a , b , Chaowei Guo a , b , Jinglin Yang a , b , Xiaoying Hou d , Hongzhi Du a , b , ? , Dahui Liu a , b , ?

2026, 18(3):746-757. DOI: https://doi.org/10.1016/j.chmed.2025.03.008

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Objective: Since ancient times, Artemisia argyi is commonly applied by folk to bathe and soak feet to disinfect and relieve itching. Moreover, abundant Chinese medical books recorded that ‘‘decocting A. argyi with bitter wine for treating dermatophytosis with excellence”. This research was designed to explore its scientific connotation. Methods: The antifungal activity against three dermatophytes of eight extracts from A. argyi was assessed in vitro. A three-variable, three-level orthogonal design was conducted to obtain the best extraction procedure of rice vinegar extract (AARV). Subsequently, Trichophyton rubrum (T. rubrum)-induced dermatophytosis mice model was used to determined the efficacy of AARV topical treatment. And then, the widely targeted metabonomic technique was employed to analyze the potential antifungal material basis of AARV. Furthermore, the mechanism of AARV against dermatophytes was explored by physiological detections, transcriptomics and real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results: AARV was the most potent anti-dermatophytic extract from A. argyi in vitro, and the best extraction procedure of AARV was optimized to the solid–liquid ratio, extraction time and rice vinegar concentration of 1:14 g/mL, 2 h and 100%, respectively. Moreover, topical treatment with AARV could alleviate skin redness, swelling and ulceration in mice, increase the number of hair follicles, and prevent the invasion of dermatophytes in hair follicles. Compared with traditional water extract, 11 unique compoundswere characterized in AARV, including five alkaloids, two flavonoids, two phenols, one sesquiterpene and one triterpene. Further mechanistic studies revealed that AARV destroyed the mycelium morphology of T. rubrum, promoted reactive oxygen species (ROS) accumulation and inhibited antioxidant enzyme activity. In addition, malate dehydrogenase (MDH) and succinate dehydrogenase (SDH) activities also decreased significantly. Transcriptome data, RT-qPCR and the determination of ergosterol content elucidated that AARV suppressed dermatophyte growth by reducing cell membrane integrity through inhibition of ergosterol and cholesterol biosynthesis pathways. And it was attributed to the downregulation of sterol 14a-demethylase (CYP51), D7 -sterol 5- desaturase (ERG3), sterol 22-desaturase (ERG5), sterol 24-C-methyltransferase (ERG6), sterol-4acarboxylate 3-dehydrogenase (ERG26),3-keto steroid reductase (ERG27), cholestenol D-isomerase (EBP) mRNA expression. Conclusion: The present study clarifies the modern scientific connotation of ‘‘decocting A. argyi with bitter wine, excellent for treating dermatophytosis” is that the rice vinegar extract of A. argyi exhibit excellent antifungal effects against dermatophytes. Importantly, it will provide the scientific support for the antidermatophytic scientific utilization of A. argyi.

22 Antibacterial and antibiofilm activity of novel nanofibers bandage formulated with Juniperus communis essential oil targeting antibiotic resistant bacterial strains

Mohannad N. AbuHaweeleh a , Ahmad Hamdan a , , Menatalla Metwally Said a , Maryam Hassiba a , Robin Augustine b , Anwarul Hassan c , Nahla O. Eltai d , Susu M. Zughaier a , ?

2026, 18(3):758-766. DOI: https://doi.org/10.1016/j.chmed.2026.05.005

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Objective: The alarming increase in antimicrobial resistance (AMR) threatens current armament of antibiotics. This global threat to public health revived the search for plant-derived antimicrobial therapeutics.Juniperus communis L. has been used in folk medicine for centuries. This study aims to examine the antibacterial and antibiofilm activity of polycaprolactone (PCL) nanofiber bandages formulate with essential oil extracted from J. communis against clinically relevant ESKAPE (Escherichia coli, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae,Acinetobacterbaumanii, Pseudomonas aeruginosa, and Enterobacter cloacae) bacterial pathogens commonly causing nosocomial infections. Methods: Bacterial growth curves and bactericidal assays were performed on antibiotic sensitive and resistant clinical bacterial strains collectively known as ESKAPE pathogens. Antibiofilm activity of Juniper essential oil (JEO) was tested against methicillin resistant S. aureus (MRSA) and E. coli individually in a 96-well plate, and the 96 well plate which contains the bacteria was incubated over night to allow biofilm formation and stained using crystal violet. The antibacterial activity of PCL-based nanofiber membrane formulated with various doses (2%, 4%, 6%, and 8%) of JEO was tested using disc diffusion method. Results: JEO dilutions (50, 25 and 12.5 lL) demonstrated a dose-dependent antibacterial activity against tested strains and significantly reduced growth after 24 h. JEO also exerted antibiofilm activity against MRSA and E. coli strains that are resistant to antibiotics. Additionally, PCL nanofiber membranes formulated with 8% JEO inhibited MRSA growth as demonstrated by large zone of inhibition on agar plate. Conclusion: JEO has antibacterial activity against ESKAPE pathogens. The potential application of JEO formulated in PCL nanofiber bandages is for wound dressing to treat surgical site infections, burns or skin ulcers.

23 Xuezhikang Capsule ameliorates ischemic stroke via multi-target modulation of neurovascular units

Xiaowen Zhang a , b , Chengchen Hou a , Yuqi Wang a , Yang Chen a , Ling Li a , Lan Xue c , Chunhui Hao c , Xi Liu c , ? , Kewu Zeng a , d , e , ?

2026, 18(3):767-769. DOI: https://doi.org/10.1016/j.chmed.2026.05.010

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24 Hepatoprotective effects of ginsenoside Rb1 from Panax ginseng on early liver injury via DNA repair activation and nuclear envelope stabilization

Fei Gao a , Haiyun Gao a , Yun Lin b , Longyan Chen a , Zheng Qi a , , Miao Yu a.

2026, 18(3):770-772. DOI: https://doi.org/10.1016/j.chmed.2026.05.001

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