Phytotherapy Research最新文献

{"title":"Research Trends and Mechanistic Insights Into Natural Medicines for Alzheimer's Disease: A Bibliometric Analysis and Narrative Review.","authors":"Maoning Wang, Xiaolian Zhang, Huaxian Yang, Jianhe Zhao, Wentao Wei, Qian Zhao, Wenjia Wang, Yunhui Hu, Jiansong Fang","doi":"10.1002/ptr.70445","DOIUrl":"https://doi.org/10.1002/ptr.70445","url":null,"abstract":"<p><p>Natural medicines have been widely investigated for Alzheimer's disease (AD), but the development of this field and the relationship between bibliometric themes and experimental evidence remain insufficiently characterized. This study aimed to map the research landscape and thematic evolution of natural medicine research for AD through bibliometric analysis and to further examine representative mechanistic evidence through a focused narrative synthesis. MethodsPublications in the Web of Science Core Collection from January 1, 2001, to April 28, 2025 were analyzed using VOSviewer and CiteSpace. Bibliometric findings were used to guide a focused narrative synthesis of original experimental studies. A total of 3316 publications involving 16,858 authors, 3594 institutions, and 106 countries or regions were identified, with China contributing the most publications. Research has shifted from acetylcholinesterase inhibition and antioxidant effects toward broader AD-related mechanisms, while computational approaches such as network pharmacology and molecular docking have become increasingly represented in this research field. Gut microbiota-related research has increased but remains an emerging direction rather than a dominant hotspot. Experimental studies of representative compounds, medicinal herbs, and formulae mainly involved Aβ and tau pathology, cholinergic dysfunction, oxidative stress, neuroinflammation, mitochondrial dysfunction, and autophagy. Clinical evidence varied substantially, with EGb 761 and Huperzine A being more extensively studied than many agents supported mainly by preclinical evidence. Computational approaches were increasingly used for hypothesis generation, but their predictions require experimental validation. Natural medicine research for AD has become increasingly mechanism-oriented and methodologically diverse. Future studies should strengthen experimental validation, improve standardization and pharmacokinetic characterization, and conduct adequately powered clinical trials to support translation of preclinical findings.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Schisandrin C Targets PPARγ to Induce Ferroptosis in Colorectal Cancer Cells and Promote M1 Macrophage Polarization.","authors":"Xiao Wei, Hong-Ping Wen, Jian-Bo Song, Jin-Fang Xu, Hong-Rui Guo","doi":"10.1002/ptr.70444","DOIUrl":"https://doi.org/10.1002/ptr.70444","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer mortality, necessitating novel therapeutic strategies. Schisandrin C (SinC), a bioactive lignan from Schisandra chinensis, exhibits diverse pharmacological activities, but its anti-CRC mechanisms are poorly understood. This study investigated the anti-CRC mechanism of SinC, focusing on PPARγ-mediated ferroptosis and macrophage polarization. Network pharmacology predicted core targets and pathways. Direct SinC-PPARγ binding was confirmed by molecular docking, CETSA, and luciferase reporter assays. In HCT116 and LoVo cells, proliferation, migration, and ferroptosis were evaluated, with mechanistic validation using a PPARγ agonist, antagonist, and shRNA. M1/M2 markers in RAW264.7 macrophages were detected. In an AOM/DSS-induced CAC mouse model, ferroptosis and macrophage polarization were assessed by Prussian blue staining, immunohistochemistry, and Western blotting. SinC directly bound and activated PPARγ, concentration-dependently inhibiting CRC cell proliferation, migration, and colony formation while inducing ferroptosis-effects reversed by liproxstatin. Mechanistically, SinC activated PPARγ, suppressed JAK2/STAT3 signaling, and downregulated SLC7A11/GPX4, effects enhanced by a PPARγ agonist and abolished by PPARγ antagonist or shRNA. SinC upregulated M1 markers and pro-inflammatory cytokines, with a predominant M1-associated activation pattern. In CAC model, SinC improved survival, inhibited tumor growth, alleviated colonic pathology, exhibited biochemical features consistent with ferroptosis, and increased intratumoral CD86⁺ cell infiltration. SinC directly binds and activates PPARγ transcriptional activity, inducing ferroptosis in CRC cells via the PPARγ-JAK2/STAT3-SLC7A11/GPX4 axis while concurrently promoting M1 macrophage polarization, exerting a dual antitumor effect. These findings support SinC as a promising therapeutic candidate for CRC.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protosappanin A Alleviates Atherosclerosis by Regulating the MDM2/GPX4 Axis-Mediated Endothelial Ferroptosis.","authors":"Jiamei Fu, Lin Zhu, Wenwei Yang, Mengnan Li, Zhixin Wu, Shude Sun, Yabin Zhou","doi":"10.1002/ptr.70443","DOIUrl":"https://doi.org/10.1002/ptr.70443","url":null,"abstract":"<p><p>Endothelial ferroptosis is a crucial pathogenic driver of atherosclerosis (AS) progression. Protosappanin A (PTA), a bioactive compound from Caesalpinia sappan L., protects cardiovascular vessels by regulating ferroptosis. However, whether PTA inhibits AS specifically through suppressing endothelial ferroptosis remains unclear. To address this, ApoE^-/- mice were fed a high-fat diet for 16 weeks to induce atherosclerosis, and PTA or simvastatin was administered daily from Week 4 through Week 16 (12 weeks of intervention). PTA markedly reduced aortic plaque area (en face Oil Red O and H&E staining) and improved serum lipid profiles (TG, TC, LDL-C, HDL-C). It also alleviated endothelial injury, evidenced by decreased VCAM-1 and ICAM-1 expression. Mechanistically, PTA ameliorated mitochondrial ferroptosis in endothelial cells, lowered intracellular Fe²⁺ and lipid peroxidation (MDA, lipid ROS), and restored the expression of GPX4, xCT, and FTH1. Immunofluorescence confirmed that PTA upregulated GPX4 within the aortic endothelium. To explore the underlying mechanism, we performed RNA-seq on ox-LDL-treated HUVECs and integrated the data with ferroptosis-related databases. MDM2 was identified as a key target, which was validated by qPCR and Western blotting. Overexpression of MDM2 activated endothelial ferroptosis and reversed the protective effects of PTA both in vitro and in vivo. Collectively, these findings demonstrate that PTA alleviates AS by suppressing endothelial ferroptosis via the MDM2/GPX4 axis.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and Pharmacodynamic Interactions Between Anti-Asthma Drugs and Medicinal Plants: A Comprehensive Review.","authors":"Emine Kocyigit, Aylin Bülbül, Betul Kocaadam-Bozkurt, Osman Bozkurt, Duygu Ağagündüz, Raffaele Capasso","doi":"10.1002/ptr.70436","DOIUrl":"https://doi.org/10.1002/ptr.70436","url":null,"abstract":"<p><p>Asthma affects 260-300 million people worldwide. About 20%-35% of patients use medicinal plants with their asthma medication, often without telling their clinicians. Disclosure rates are low; up to 42% of asthma outpatients use herbal products, with no records in their charts. Previous reviews discussed herb-drug interactions and asthma phytotherapy separately. There is no combined pharmacokinetic, pharmacodynamic, and toxicological evidence for all modern anti-asthma agents. This review closes that gap. It draws from mechanistic, preclinical, and clinical data. It looks at eight common botanicals: Glycyrrhiza glabra, Curcuma longa, Nigella sativa, Boswellia serrata, Tylophora indica, Adhatoda vasica, Astragalus membranaceus, and Piper nigrum. The review explains how these botanicals affect cytochrome P450 isoenzymes, Phase II conjugative enzymes, and membrane transporters, including P-glycoprotein. It also considers shared adrenergic, glucocorticoid-receptor, and inflammatory targets of inhaled corticosteroids, β₂-agonists, leukotriene receptor antagonists, theophylline, and biologic agents. These interactions create clinical hazards. For example, Hypericum perforatum increases CYP3A4 activity by up to 11-fold and can destabilize theophylline and corticosteroid levels. Ephedra sinica causes dose-dependent sympathomimetic toxicity, which worsens β₂-agonist cardiovascular risk. Glycyrrhiza glabra may trigger pseudoaldosteronism and hypokalaemia by inhibiting 11β-hydroxysteroid dehydrogenase type 2. Ginkgo biloba has been tied to bleeding events. Turmeric, previously seen as safe, now appears in drug-induced liver injury registries. Compositional variability adds to the risk; for example, hyperforin content can range from 0.01% to 1.89%, and ephedrine content varies by more than 12-fold across products. This review places its findings in the context of the WHO Global Traditional Medicine Strategy 2025-2034. It identifies important herb-anti-asthma drug pairs, defines monitoring endpoints, and proposes a pharmacogenetically informed framework for safely integrating medicinal plants into asthma care.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148901036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catechins and Their Effect on the Gut Microbiome in Health and Cancer.","authors":"Prakash Monika, Bindu Sadanandan, Honnamachanahalli Ramachandraiah Tejashree, Maitreyi Darbha, Kirti Gupta, Srinivas Reneeka","doi":"10.1002/ptr.70435","DOIUrl":"https://doi.org/10.1002/ptr.70435","url":null,"abstract":"<p><p>Catechins are a group of flavonoids found primarily in green tea, fruits, and berries; they play a significant role in the modulation of the gut microbiota, thereby having an impact on gut health and cancer prevention. Owing to their low bioavailability, catechins are transformed by the gut microbiota into various bioactive metabolites such as valerolactones and glucuronides, which support the growth of several beneficial bacterial species including Bifidobacterium and Lactobacillus while inhibiting harmful strains like Clostridium difficile and Escherichia coli. These interactions enhance metabolic balance, reduce inflammation, and help maintain gut homeostasis, which is critical for preventing gut dysbiosis. Dysbiosis is characterized by a shift from symbiotic to pathogenic microbial populations and is closely associated with cancer development, especially in the gut. This review explores how catechins, particularly epigallocatechin gallate (EGCG), contribute to cancer prevention by promoting a symbiotic microbial environment, supporting immune modulation, and inhibiting inflammatory pathways. By examining the role of catechins in both health and cancer, this paper aims to emphasize their therapeutic potential as dietary supplements in maintaining gut health and reducing cancer risk.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating Host Lipid Metabolism via Gut Microbiota: Therapeutic Potential of Plant-Derived Compounds.","authors":"Lijun Wang, Ji Cheng, Weilong Peng, Yiqian Chen, Shifeng Pan, Yao Lu","doi":"10.1002/ptr.70402","DOIUrl":"10.1002/ptr.70402","url":null,"abstract":"<p><p>Lipid metabolic imbalance is a major contributor to metabolic disorders in humans and livestock, creating an urgent need for safe and effective regulatory approaches. Plant-derived compounds, characterized by favorable bioavailability and low toxicity, serve as promising candidates that regulate host lipid metabolism through dynamic crosstalk with the gut microbiota. This review systematically investigates the bidirectional crosstalk between plant bioactive compounds (e.g., polysaccharides, flavonoids, saponins and polyphenols) and the gut microbiota. We detail how gut microbes metabolize these compounds to enhance their bioactivity and bioavailability, while plant extracts reshape microbial community structure to enrich beneficial taxa. Furthermore, we elucidate the mechanisms underlying lipid metabolism regulation, focusing on three critical signaling pathways: (1) SCFAs-GPR43/41 signaling, (2) TLR4/NF-κB inflammation suppression, and (3) bile acid-FXR axis modulation. Collectively, this review synthesizes emerging evidence on plant-microbiota interactions as a novel therapeutic strategy to restore lipid homeostasis in animal models, offering foundational insights for agricultural and biomedical applications.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5519-5537"},"PeriodicalIF":8.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148284039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poria cocos Polysaccharides Protect Against Contrast-Induced Renal Injury Through Activating CaMKK2/AMPK/PGC-1α Signaling Pathway.","authors":"Daolun Yu, Kai Ge, Naidong Chen, Yinuo Gong, Hangbo Xu, Zongmeng Zhang","doi":"10.1002/ptr.70409","DOIUrl":"10.1002/ptr.70409","url":null,"abstract":"<p><p>The necessity of iodinated contrast agents in radiographic diagnosis comes with an increased risk of kidney injury. The sclerotium of Poria cocos (Schw.) Wolf, a traditional Chinese medicine, exhibits anti-inflammatory and diuretic pharmacological properties. Its extracted polysaccharides demonstrate anti-apoptotic, antioxidant, and anti-inflammatory activities. This study aimed to investigate the effects and potential mechanisms of Poria cocos polysaccharides (PCP) on contrast-induced acute kidney injury (CI-AKI). The purified PCP was characterized using FTIR and monosaccharide analysis. A CI-AKI mouse model was established to evaluate its preventive effects via oral gavage. Mitochondrial structure, function, and biogenesis were assessed by measuring mitochondrial membrane potential (MMP), ROS, ATP, and mitochondrial DNA copy number. Antioxidant capacity and apoptosis levels were evaluated by detecting 8-OHdG, caspase 3/7 activity, cleaved-PARP, MDA, and GSH. Finally, the mechanism of action of PCP was analyzed using qPCR and immunoblotting. The results showed that PCP significantly mitigated CI-AKI by inhibiting contrast-induced apoptosis and oxidative stress in kidney tissue. Furthermore, PCP maintained mitochondrial homeostasis in the kidneys by enhancing mitochondrial biogenesis and antioxidant capacity. These findings were consistent with in vitro data. Notably, PGC-1α was identified as a key factor in the nephroprotective effects of PCP, with its activation attributed to the CaMKK2-AMPK signaling pathway. These findings suggest that PCP offers significant benefits in mitigating CI-AKI by enhancing antioxidant defenses and promoting mitochondrial biogenesis through activation of the CaMKK2/AMPK/PGC-1α signaling pathway in the kidney. Therefore, PCP could be a potential preventive agent for CI-AKI.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5501-5518"},"PeriodicalIF":8.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148272573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumol Inhibits the Invasion and Migration of Breast Cancer via miR-206/NCL/ERα36.","authors":"Xiaojuan Li, Muzhao Tian, Luwei Zhou, Hongfang Ding, Riqiu Zhang, Xu Chen, Juan Wang","doi":"10.1002/ptr.70375","DOIUrl":"10.1002/ptr.70375","url":null,"abstract":"<p><p>Breast cancer (BC) is a highly heterogeneous and aggressive disease with high mortality. Curcumol, a major bioactive component from Curcumae kwangsiensis, has shown antitumor activity by targeting nucleolin (NCL) and its interaction with ERα36. NCL is an RNA-binding protein that interacts with miR-206, a tumor-suppressive miRNA that inhibits EMT and invasion by regulating target gene expression. However, whether curcumol's effect on BC invasion and migration, as well as the NCL/ERα36 interaction, is regulated by miR-206 remains unclear. Cell migration and invasion were assessed using wound healing and transwell assays. Dual-luciferase reporter and RIP assays were performed to confirm NCL as a direct target of miR-206. Western blotting and qRT-PCR were used to evaluate protein and miRNA expression. Animal experiments were conducted to explore the inhibitory effect of curcumol on invasion and migration in vivo. Curcumol significantly inhibited the invasion and migration of breast cancer cells, while potentiating the inhibitory effects of NCL knockdown on these processes. NCL was identified as a downstream target of miR-206, and curcumol inhibits the invasion and migration of breast cancer cells via downregulating NCL expression and is associated with increased miR-206 levels. Moreover, curcumol inhibits the invasion and migration of breast cancer cells by downregulating the NCL/ERα36 interaction. The anti-breast cancer effect of curcumol is related to its regulation of the expression of miR-206 and NCL and inhibits the invasion and migration of breast cancer via the miR-206/NCL/ERα36 axis.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5566-5580"},"PeriodicalIF":8.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148308985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salvianolic Acid C Protects Against Hepatic Ischemia-Reperfusion Injury via Heat Shock Protein 90α-Mediated Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway.","authors":"Pingping Qiao, Alimu Tulahong, Xinlu Xu, Tiemin Jiang, Ruiqing Zhang, Yanze Lin, Zhongdian Yuan, Rexiati Ruze, Yingmei Shao","doi":"10.1002/ptr.70437","DOIUrl":"https://doi.org/10.1002/ptr.70437","url":null,"abstract":"<p><p>Hepatic ischemia-reperfusion injury (HIRI) is a major challenge in liver surgery, and effective pharmacological interventions are lacking. Salvianolic acid C (SaC) has shown protective effects in various pathologies, but its role in HIRI remains unclear. This study investigated whether SaC protects against HIRI and elucidated the underlying mechanisms. Bioinformatics analysis of GSE151648 identified differentially expressed heat shock proteins (HSPs) and associated pathways. Molecular docking predicted SaC binding to HSP90α and AKT. A murine HIRI model was established with SaC (10 mg/kg, i.p.) pretreatment for 7 days. Histology, serum transaminases, and oxidative stress markers assessed liver injury. HSP90α inhibition used 17-AAG; in vitro hypoxia/reoxygenation (H/R) experiments used AML12 hepatocytes. Clinical validation used paired liver tissues from patients undergoing ex vivo liver resection and autotransplantation. Twenty-one HSP genes were differentially expressed, with HSP90α as a core hub gene in the PI3K/AKT pathway. SaC showed high binding affinity for HSP90α (-8.7 kcal/mol) and p-AKT1 (-10.9 kcal/mol). In mice, SaC upregulated HSP90α, reduced necrosis and serum transaminases, decreased MDA and increased GSH and SOD, suppressed TNF-α, IL-1β, and IL-6, and reduced apoptosis (Bax/Bcl-2, cleaved caspase-3), while activating PI3K/AKT. These effects were abolished by 17-AAG and confirmed in H/R-treated AML12 cells. HSP90α was also upregulated in post-transplant human livers. SaC protects against HIRI by upregulating HSP90α and activating PI3K/AKT, thereby alleviating oxidative stress, inflammation, apoptosis, and necrosis. These findings support SaC as a potential therapeutic strategy for HIRI.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol Ameliorates Hypertrophic Scar Formation by Regulating ASIC3-Mediated Fibroblast-Macrophage Crosstalk: A Mechanistic Study.","authors":"Zili Sun, Suzhou Huang, Xingxing Lu, Yiheng Zhang, Xin Ding, Tianle Ma, Bingfeng Yuan, Shan Yu, Li Wu","doi":"10.1002/ptr.70397","DOIUrl":"10.1002/ptr.70397","url":null,"abstract":"<p><p>To elucidate the mechanism by which Resveratrol (Res) ameliorates hypertrophic scar (HS) formation by targeting acid-sensing ion channel 3 (ASIC3) to modulate macrophage-fibroblast (FB) crosstalk. A rabbit-ear HS model was established in vivo. Hematoxylin-eosin (H&E) staining, Masson staining, immunofluorescence (IF), Western blot (WB), and quantitative real-time PCR (RT-qPCR) were used to assess the effects of Res on scar hyperplasia, collagen deposition, FB activation, and macrophage polarization. In vitro, FB activation was stimulated by combined treatment with TGF-β1 and lactic acid, and a Transwell co-culture system comprising FB and human monocyte-derived M0 macrophages was established. Scratch assay, FCM, IF, and WB were performed to assess the impacts of Res on FB activation, migration, and macrophage polarization. Additionally, ASIC3 gene knockout experiments were conducted both in vivo and in vitro to confirm the mechanism underlying Res-mediated HS improvement. In vitro, Res significantly inhibited FB migration in a dose-dependent manner and downregulated the protein expression of α-SMA, COL1A1, COL3A1, reduced M-CSF secretion, suppressed macrophage polarization toward the M2 phenotype, and decreased TGF-β1 mRNA expression. It also blocked activation of the PI3K/Akt signaling pathway downstream of ASIC3. These effects were completely abolished after ASIC3 gene knockdown. In vivo, Res significantly reduced the scar elevation index (SEI) in rabbit-ear HS. It improved collagen fiber arrangement and decreased collagen deposition. It markedly inhibited M2 macrophage polarization and TGF-β1 mRNA expression. After ASIC3 knockout, the anti-HS effects of Res, as well as its regulatory effects on macrophage polarization and fibrotic factors, were abrogated. Res ameliorates HS by inhibiting ASIC3 expression. This disrupts the ASIC3-M-CSF-TGF-β1 positive feedback loop. It restores the balance of macrophage polarization, inhibits FB activation, reduces abnormal collagen deposition, and ultimately attenuates HS formation.</p>","PeriodicalId":20110,"journal":{"name":"Phytotherapy Research","volume":" ","pages":"5389-5404"},"PeriodicalIF":8.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}