Phytomedicine最新文献

{"title":"YTHDF2-orchestrated m6A methylation of BECN1 induces Scoparone-mediated hepatic stellate cell ferroptosis to attenuate liver fibrosis","authors":"Yuqi Sun ,&nbsp;Yanshuang Zhuang ,&nbsp;Kaiwen Cheng ,&nbsp;Yuyao Wei ,&nbsp;Mengran Li ,&nbsp;Ji Xuan ,&nbsp;Shizhong Zheng ,&nbsp;Mei Guo ,&nbsp;Zili Zhang","doi":"10.1016/j.phymed.2026.157912","DOIUrl":"10.1016/j.phymed.2026.157912","url":null,"abstract":"<div><h3>Background</h3><div>Liver fibrosis represents a dynamically reversible pathological process arising as an adaptive repair response to chronic hepatic insults. Scoparone (SCO), an active constituent of artemisia, has demonstrated therapeutic potential across diverse liver diseases, but its antifibrotic mechanism remains unclear.</div></div><div><h3>Purpose</h3><div>This study aims to elucidate the molecular mechanism by which SCO ameliorates liver fibrosis through m⁶A epitranscriptomic regulation of hepatic stellate cell (HSC) ferroptosis.</div></div><div><h3>Methods</h3><div>Murine liver fibrosis models and human HSC cells were employed to evaluate the therapeutic effects of SCO on liver fibrosis. Single-cell sequencing, spatial transcriptome sequencing, transcriptome sequencing, immunoprecipitation and laser confocal were used to investigate the potential molecular mechanisms.</div></div><div><h3>Results</h3><div>Animal experiments and cellular studies showed that SCO exhibited potent antifibrotic effects, which was attributed to the induction of HSC ferroptosis through m⁶A modification. Integrative transcriptomic and bioinformatic analyses identified BECN1 as a key target for m⁶A methylation regulation of ferroptosis. Mechanistically, SCO may interact with the ASN462 residue of YTHDF2, enhancing its protein stability and expression. Elevated YTHDF2 can facilitate translation of BECN1 mRNA by recognizing m⁶A methylation at the A100 site within the 5′-UTR, leading to SLC7A11 activity inhibition and subsequent ferroptotic cell death in HSCs. Clinically, YTHDF2 and BECN1 expression was downregulated in fibrotic liver tissue specimens, which was associated with a poor prognosis.</div></div><div><h3>Conclusions</h3><div>These results reveal a novel epitranscriptomic mechanism by which SCO induces HSC ferroptosis to attenuate liver fibrosis by promoting the formation of BECN1-SLC7A11 complex through YTHDF2-mediated m⁶A modification. Thess findings molecular insights and therapeutic rationales for SCO-based antifibrotic therapies.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157912"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining network pharmacology and multi-omics reveals the role of Shengdihuang-Huangqi herb pair in alleviating type 2 diabetes mellitus","authors":"Xianglin Cao ,&nbsp;Yuhan Shang ,&nbsp;Mengyao Qu ,&nbsp;Qiuxia Kang ,&nbsp;Yifan Xu ,&nbsp;Qiang Wang ,&nbsp;Shuaishuai Xie ,&nbsp;Daogang Guan ,&nbsp;Jianjun Chen","doi":"10.1016/j.phymed.2026.157900","DOIUrl":"10.1016/j.phymed.2026.157900","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to elucidate the therapeutic mechanisms of the Shengdihuang-Huangqi (SDH<img>HQ) herbal pair in type 2 diabetes mellitus (T2DM) by integrating network pharmacology, transcriptomics, and metabolomics, together with experimental validation, to identify key bioactive compounds and explore their potential targets.</div></div><div><h3>Methods</h3><div>Active components of SDH<img>HQ were screened from multiple databases, potential targets were predicted through network pharmacology, and a compound-target network was constructed by cross-referencing with T2DM-related genes. KEGG and GO enrichment analyses were then performed to identify key signaling pathways. Transcriptomic profiling of liver tissues from T2DM rats was carried out using RNA sequencing, while serum analysis was conducted via metabolomics. Transcriptomic and metabolomic data were integrated to explore gene-metabolite associations and identify potential pathways of SDH<img>HQ action. Experimental validation involved measurements of fasting blood glucose, serum lipid levels, histopathology, and hepatic gene expression in T2DM rats, as well as glucose uptake and glycogen synthesis assays in insulin-resistant HepG2 cells.</div></div><div><h3>Results</h3><div>Network pharmacology analysis identified six bioactive compounds—quercetin, kaempferol, formononetin, apigenin, catalpol, and acteoside—as potential major contributors to the therapeutic effects of SDH<img>HQ against T2DM. <em>In vivo</em> experiments demonstrated that SDH<img>HQ significantly ameliorated hyperglycemia, dyslipidemia, and tissue damage in T2DM rats. Multi-omics analysis and qPCR validation further indicated that SDH<img>HQ ameliorates T2DM by modulating the insulin resistance, AMPK, and PPAR signaling pathways, thereby influencing hepatic glycogen synthesis and glucose uptake.</div></div><div><h3>Conclusions</h3><div>In conclusion, SDH<img>HQ ameliorates T2DM by modulating glucose metabolism through the INS/IRS2/AKT2 and FOXO1 pathways and lipid metabolism via the SREBP1c/FAS/ACC1 and PPARα/CD36 pathways, providing molecular evidence for its therapeutic potential.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157900"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rg2 ameliorates acute cold exposure/rewarming-induced myocardial injury via modulating HMGB1/TLR4/NF-κB and PGC-1α signaling pathways: Role of SIRT1.","authors":"Shunfang Zuo, Wenwen Fu, Wenli Ma, Huifeng Wang, Shuting Feng, Han Sun, Zihao Zhang, Linyu Li, Yan Xue, Huali Xu","doi":"10.1016/j.phymed.2026.157997","DOIUrl":"10.1016/j.phymed.2026.157997","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Acute cold exposure (ACE) is a significant environmental stressor that markedly increases the risk of cardiovascular complications; however, the precise mechanisms underlying the resultant myocardial injury remain incompletely understood. Ginsenoside Rg2 (Rg2), a key bioactive component of Panax ginseng, confers significant cardioprotective benefits. Despite this, the therapeutic potential and specific mechanisms of Rg2 in attenuating acute cold exposure/rewarming (ACE/R)-induced myocardial injury require further clarification.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Purpose: &lt;/strong&gt;The objective of this study was to clarify the cardioprotective efficacy of Rg2 and delineate the underlying molecular mechanisms in rats with ACE/R-induced myocardial injury.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In vivo and in vitro models of cold-induced injury were established, including an ACE/R rat model and a mild hypothermia (MH) model utilizing primary rat cardiomyocytes. The cardioprotective effects of Rg2 were evaluated in vivo using functional assessments (echocardiography and hemodynamics), histological analysis (H&E staining), ultrastructural examination (transmission electron microscopy), and hemorheological, biochemical, and ELISA analyses. In vitro, cell viability and cytotoxicity were assessed using CCK-8 and LDH release assays. An integrated approach was employed to elucidate the mechanisms underlying Rg2 action. Initially, proteomics, molecular docking, molecular dynamics simulations, and CETSA were performed to verify the direct interaction between Rg2 and SIRT1. Subsequently, immunohistochemistry, RT-qPCR, western blot, and Co-IP assays were conducted to evaluate pathway activation in both rat myocardial tissue and primary cardiomyocyte samples. Finally, the indispensable role of SIRT1 in mediating the therapeutic effects of Rg2 was definitively established by integrating genetic ablation (mediated by AAV9 and siRNA) and pharmacological inhibition (using EX527) strategies across both in vitro and in vivo experimental systems.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Rg2 treatment significantly attenuated ACE/R-induced cardiac injury, as evidenced by improved cardiac function, diminished myocardial inflammation, and mitigated mitochondrial damage. Mechanistically, Rg2 upregulated SIRT1 expression, which suppressed inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway and concurrently ameliorated mitochondrial dysfunction by enhancing mitochondrial biogenesis involving the PGC-1α pathway. Furthermore, both pharmacological inhibition and genetic knockdown of SIRT1 significantly abrogated the cardioprotective effects of Rg2 against ACE/R-induced myocardial injury.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study provides the first evidence that ginsenoside Rg2 has considerable cardioprotective effects against ACE/R. The cardioprotective mechanism is mediated through SIRT1 activation, which subsequently suppresses the HMGB1/TLR4/NF-κB-mediated inflammatory ca","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"157997"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sulforaphane-rich aqueous broccoli seed extract suppresses diet-induced obesity via 5-HT2A/AMPK signaling in mice","authors":"Yong Jae Jeon ,&nbsp;Junkyu Park ,&nbsp;Keun-Tae Park ,&nbsp;Heejoon Jo ,&nbsp;Soohyun Um ,&nbsp;Hyeongju Jeong ,&nbsp;Kyuho Moon ,&nbsp;Seung-Su Lee ,&nbsp;Jinbong Park ,&nbsp;Ji Hoon Jung ,&nbsp;Seong-Gyu Ko ,&nbsp;Kyungjin Lee ,&nbsp;Woojin Kim","doi":"10.1016/j.phymed.2026.157935","DOIUrl":"10.1016/j.phymed.2026.157935","url":null,"abstract":"<div><h3>Background</h3><div>Obesity remains a major global health challenge, and current pharmacotherapies have limitations in long-term efficacy, safety, and cost. Broccoli (<em>Brassica oleracea</em> L. var. <em>italica</em>) seeds are a rich source of sulforaphane (SFN), which has demonstrated anti-obesity effects. However, the bioavailability of SFN from broccoli seeds is limited by suboptimal conversion conditions and competing nitrile-formation pathways.</div></div><div><h3>Purpose</h3><div>This study aims to standardize a high-yield, SFN-rich broccoli seed hydrolysate (BSH), to evaluate its anti-obesity efficacy in mice fed a high-fat diet (HFD), and to elucidate its mechanism via molecular docking and molecular dynamics (MD).</div></div><div><h3>Methods</h3><div>SFN hydrolysis was optimized by Liquid chromatography–high-resolution mass spectrometry (LC–HRMS) and High-performance liquid chromatography (HPLC) across pH, temperature, time, and L-ascorbic acid; 5-hydroxytryptamine receptor 2A (5-HT2A) binding was probed by network pharmacology, molecular docking, and 100 ns MD. HFD-fed male C57BL/6 mice (n = 6 per group) received oral broccoli seed water extract (BWE), BSH, or SFN for 8 weeks. Anti-obesity efficacy was assessed by body/tissue weights, micro-computed tomography (Micro-CT), histology, and serum lipid profiling, while 5-HT2A, adenosine monophosphate–activated protein kinase (AMPK) phosphorylation and other markers in epididymal white adipose tissue (eWAT) and liver were assessed by quantitative real-time PCR (qRT-PCR) and Western blot.</div></div><div><h3>Results</h3><div>SFN production from broccoli seeds was maximized under two hydrolysis regimes: short-term (pH 4 at 35°C for 2 h) and long-term (pH 5 at 25°C for 24 h). In silico analyses predicted stable binding of the sulforaphane–glutathione conjugate (SFN–GSH) to 5-HT2A. In HFD-fed mice, BSH (40–800 mg/kg, p.o.) dose-dependently attenuated HFD-induced body weight gain (800 mg/kg vs HFD, p &lt; 0.001). BWE 400 mg/kg and BSH 40 mg/kg showed broadly comparable effects on body weight. Furthermore, gene and protein analyses in eWAT and liver showed 5-HT2A (Htr2a) suppression, restored AMPK phosphorylation, and downregulation of lipogenic regulators. However, co-administration of the AMPK inhibitor Compound C (5 mg/kg, i.p.) with BSH abolished these BSH-induced effects. Oral administration of a sulforaphane standard (1–10 mg/kg) produced similar effects to BSH (10 mg/kg vs HFD, p &lt; 0.01), suggesting that the anti-obesity effect of BSH is mediated primarily by SFN.</div></div><div><h3>Conclusions</h3><div>In this study, SFN-rich BSH ameliorated obesity in HFD-fed mice via a peripheral 5-HT2A suppression–AMPK activation axis. However, further mechanistic clarification will require studies to more precisely define the role of 5-HT2A in adipocytes.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157935"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Huodan Qinghua formula inhibits CD36 membrane localisation via the TGR5-DHHC4 pathway to ameliorate lipotoxic damage in diabetic cardiomyopathy","authors":"Xinbiao Fan ,&nbsp;Jun Ge ,&nbsp;Yongchun Liang ,&nbsp;Zhipeng Yan ,&nbsp;Xiaofei Geng ,&nbsp;Meng Li ,&nbsp;Xitong Sun ,&nbsp;Boyu Zhu ,&nbsp;Wenyu Shang ,&nbsp;Yunfeng Jia ,&nbsp;Yixuan Zhao ,&nbsp;Yuxin Kang ,&nbsp;Zheng Zhang ,&nbsp;Yue Hu ,&nbsp;Junping Zhang","doi":"10.1016/j.phymed.2025.157761","DOIUrl":"10.1016/j.phymed.2025.157761","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Diabetic cardiomyopathy (DCM) is a diabetes-associated cardiac complication with a steadily increasing incidence and remains a major clinical challenge due to its complex and recurrent pathogenesis. Huodan Qinghua formula (HDQH), a proprietary herbal formulation, has been extensively employed in clinical practice for over a decade in the treatment of diabetic cardiovascular diseases, with demonstrated efficacy in improving cardiac function and prognosis. Nevertheless, the underlying mechanisms of action and pharmacological effects of HDQH in the amelioration of DCM remain to be fully elucidated.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;To investigate whether HDQH alleviates cardiac lipotoxicity by reducing fatty acid uptake (FAU), thereby elucidating its underlying mechanism in the treatment of DCM.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to identify HDQH and its bioactive constituents &lt;em&gt;in vivo.&lt;/em&gt; Network pharmacology and molecular docking techniques were utilized to predict the key therapeutic targets and signaling pathways through which HDQH exerts its effects on DCM. These predictions were subsequently validated using both &lt;em&gt;in vivo&lt;/em&gt; and &lt;em&gt;in vitro&lt;/em&gt; experiments. A diabetic mouse model was established in C57BL/6 J mice via a high-fat diet combined with streptozotocin (STZ) administration, followed by daily oral gavage of HDQH for 12 weeks. Cardiac function and morphology were assessed via echocardiography, Masson's trichrome staining, and hematoxylin and eosin (HE) staining. Myocardial lipid accumulation and FAU were examined using Oil Red O staining and fluorescently labeled fatty acids (FAs), respectively. Levels of total bile acids, insulin, NT-proBNP, and serum lipids were quantified using ELISA and biochemical assays, while free fatty acids (FFAs) and reactive oxygen species (ROS) were also measured. Potential molecular mechanisms were explored using Western blot and real-time quantitative PCR (RT-qPCR). H9C2 cells were exposed to palmitic acid (PA), and the effects of HDQH were further examined through pharmacological activation and inhibition of target protein expression.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Sixteen compounds and metabolites were identified in the plasma following HDQH administration, with major constituents including palmatine, bavachromanol, loganetin, oxyberberine, and neocryptotanshinone. Network pharmacology and molecular docking analyzes suggested that HDQH might exert potential therapeutic effects on DCM by modulating TGR5 receptor-associated signaling pathways. HDQH significantly improved cardiac function in DCM mice while effectively reducing myocardial hypertrophy, fibrosis, and lipid deposition. Concurrently, it elevated total bile acid levels whilst decreasing FFA and ROS levels. WB and RT-qPCR analyzes demonstrated that the inhibition of cardiac lipotoxicity by HDQH was closely","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157761"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146181870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zhi-Chuan-Ling alleviates OVA-induced allergic asthma by suppressing M2 macrophage polarization via the PI3K/AKT/mTOR/STAT6 pathway","authors":"Sihui Xing ,&nbsp;Huidan Chen ,&nbsp;Ling Wang ,&nbsp;Siye Lv ,&nbsp;Jinpu Zhu ,&nbsp;Zhongtian Wang ,&nbsp;Jing Han ,&nbsp;Haiyang Zhang ,&nbsp;Ruikang Fang ,&nbsp;Jiali Wu ,&nbsp;Fengyan Shao ,&nbsp;Jicheng Han ,&nbsp;Liping Sun","doi":"10.1016/j.phymed.2026.157911","DOIUrl":"10.1016/j.phymed.2026.157911","url":null,"abstract":"<div><h3>Background</h3><div>Allergic asthma, predominantly driven by Th2 immune responses, is a chronic respiratory disease that poses a significant threat to human health. Zhi-Chuan-Ling (ZCL), a traditional Chinese medicine widely used for the treatment of asthma and wheezy bronchitis, has been shown to relieve airway constriction and suppress airway inflammation. However, its mechanisms in regulating macrophage polarization, a key Th2-driven inflammatory process, remain unclear.</div></div><div><h3>Purpose</h3><div>This study aimed to assess the therapeutic effects of ZCL on allergic asthma and to investigate its molecular mechanisms in modulating macrophage polarization.</div></div><div><h3>Methods</h3><div>The chemical profile of ZCL was characterized by high-performance liquid chromatography (HPLC). An ovalbumin (OVA)-induced mouse model of allergic asthma was established to assess the anti-asthmatic effects of ZCL. Mechanistic studies included hematoxylin-eosin (H&amp;E) and Masson’s trichrome (MT) staining, immunofluorescence (IF), ELISA, flow cytometry (FCM), transcriptomic profiling, Western blotting (WB), and in silico molecular docking to predict binding interactions of key ZCL compounds with target proteins involved in M2 macrophage polarization and airway inflammation.</div></div><div><h3>Results</h3><div>ZCL treatment significantly alleviated asthma symptoms and reduced airway inflammation in vivo. Mechanistically, ZCL inhibited M2 macrophage polarization by modulating the PI3K/AKT/mTOR/STAT6 signaling pathway. Molecular docking analysis revealed favorable binding of major ZCL compounds to PI3K, AKT, mTOR, and STAT6, supporting their potential role in modulating these signaling molecules.</div></div><div><h3>Conclusion</h3><div>ZCL protects against allergic asthma by suppressing M2 macrophage polarization through the PI3K/AKT/mTOR/STAT6 axis and by directly interacting with key pathway proteins, thereby attenuating airway inflammation and remodeling. These findings provide both functional and molecular evidence for the therapeutic potential of ZCL in allergic asthma.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157911"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146116350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quercetagitrin targets EIF3D to activate NCOA4-mediated ferritinophagy-dependent ferroptosis for the treatment of non-small cell lung cancer","authors":"Xinglinzi Tang ,&nbsp;Feiyan Wu ,&nbsp;Huijuan Rao ,&nbsp;Xinyi Luo ,&nbsp;Guixing Zhang ,&nbsp;Xin Lai ,&nbsp;Caizhi Li ,&nbsp;Jiansong Fang ,&nbsp;Hang Li","doi":"10.1016/j.phymed.2026.157914","DOIUrl":"10.1016/j.phymed.2026.157914","url":null,"abstract":"<div><h3>Background</h3><div>Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer. Although traditional treatment methods such as surgery, chemotherapy, and radiotherapy can extend patient survival to some extent, they still present significant challenges due to their limited efficacy and substantial side effects. Ferroptosis, a form of iron-dependent programmed cell death, has been shown to exhibit considerable potential in the treatment of NSCLC. However, the molecular mechanisms underlying ferroptosis and how to safely and effectively induce it remain to be fully explored. This study aims to investigate the mechanism by which the natural flavonoid compound Quercetagitrin (Que) regulates the ferritinophagy-ferroptosis pathway to suppress NSCLC and to identify its molecular targets.</div></div><div><h3>Methods</h3><div>This study evaluated the selective toxicity of Que against NSCLC cells (A549, PC9) and normal lung epithelial cells (BEAS-2B) using <em>in vitro</em> assays, including CCK-8, colony formation, and flow cytometry. Key pathways related to ferritinophagy and ferroptosis were identified through transcriptomic analysis and KEGG pathway analysis. Fluorescence imaging, Western blot (WB) and BODIPY C11 staining were used to assess the levels of ferritinophagy and ferroptosis in cells. Limited proteolysis-mass spectrometry (LiP-MS) and molecular dynamics simulations were employed to identify the direct targets of Que. Gene knockdown and overexpression experiments were conducted to verify that Que targets eukaryotic translation initiation factor 3 subunit D (EIF3D) and regulates the activation of nuclear receptor coactivator 4 (NCOA4) -mediated ferritinophagy. <em>In vivo</em> experiments using xenograft mouse models assessed the antitumor effect and safety of Que.</div></div><div><h3>Results</h3><div>Que selectively inhibited the proliferation and colony formation of NSCLC cells while showing minimal toxicity to normal lung epithelial cells. It promoted the release of Fe²⁺ and lipid peroxidation by activating the NCOA4-dependent ferritinophagy pathway, while simultaneously inhibiting the expression of ferroptosis markers such as glutathione peroxidase 4 (GPX4). LiP-MS and molecular dynamics simulations confirmed EIF3D as a direct target of Que. Knockdown of EIF3D mimicked the antitumor effect of Que, whereas overexpression of EIF3D diminished its antitumor effect. <em>In vivo</em>, Que significantly inhibited tumor growth without observable toxicity, accompanied by upregulation of NCOA4 and LC3 II, and downregulation of EIF3D and GPX4.</div></div><div><h3>Conclusion</h3><div>Que exerts significant antitumor effects in NSCLC by targeting EIF3D to activate NCOA4-mediated ferritinophagy and ferroptosis. This study reveals a novel mechanism involving the EIF3D-NCOA4 axis in the regulation of ferritinophagy-dependent ferroptosis, providing a potential therapeutic strategy for the treatment of NSCLC.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157914"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting muscle-bone crosstalk with hormone-like peptides: Systems approach reveals RGHGP-mediated suppression of LAMB1-MAPK osteoclastogenesis","authors":"Yu-jie Xi ,&nbsp;Rui Cai ,&nbsp;Shao-wei Hu ,&nbsp;Bo Zhang ,&nbsp;He Xu ,&nbsp;Hong-yan Zhao ,&nbsp;Hong-jun Yang ,&nbsp;Fei-fei Guo","doi":"10.1016/j.phymed.2026.157926","DOIUrl":"10.1016/j.phymed.2026.157926","url":null,"abstract":"<div><h3>Background</h3><div>Clinical evidence suggests a strong association between bone and muscle; however, the underlying mechanisms beyond the physiological relationship remain unclear.</div></div><div><h3>Objective</h3><div>To explore the pathological changes between bone and muscle using a bilateral ovariectomy (OVX) model and to evaluate the therapeutic potential of Rengong hugu power (RGHGP) as a peptide-derived intervention in regulating muscle–bone health.</div></div><div><h3>Methods</h3><div>Dual-tissue transcriptomics, network construction, and therapeutic intervention experiments were performed. Tissue-specific ligand–receptor and signaling pathway interaction networks were constructed based on dual-tissue transcriptomics sequencing data. Crucial ligands and receptors were identified to provide a foundation for interorgan communication. RGHGP was administered to regulate muscle–bone health, and its role as a ligand-like molecule binding to major receptors and pathways was verified. Potential peptides coordinating muscle–bone health were predicted. Weight, mass, imaging, and histopathological changes were assessed. TRAP staining, protein–peptide docking, and in vitro assays were used to evaluate the role of RGHGP and Laminin subunit beta 1 (LAMB1) on bone metabolism and osteoclastogenesis.</div></div><div><h3>Results</h3><div>OVX induced osteoporosis and muscle atrophy, whereas RGHGP reversed these pathological changes. Six myokines, represented by LAMB1 and connective tissue growth factor (CTGF), mediated bone metabolism through the mitogen-activated protein kinases(MAPK) pathway. In the OVX model, muscle-secreted LAMB1 and CTGF were upregulated in bone, activating MAPK signaling (phosphorylation of p38 and JNK) and increasing osteoclasts, as detected by TRAP staining. RGHGP treatment repressed LAMB1/CTGF expression, MAPK pathway activation, and osteoclast number. In vitro studies showed that the recombinant protein LAMB1 (rLAMB1) promotes osteoclast formation by activating the MAPK pathway. In contrast, the therapeutic peptide RGHGP effectively blocks this process. This therapeutic effect is structurally supported by protein–peptide docking, which confirmed the ability of RGHGP to bind key receptors in MAPK receptor signaling.</div></div><div><h3>Conclusion</h3><div>This study establishes a ligand (LAMB1)–receptor–pathway (MAPK) model for muscle–bone crosstalk, highlighting the role of muscle-derived ligands in counteracting muscle atrophy and regulating osteoclasts and osteoporosis. RGHGP-derived peptides act as muscle-mimetic ligands, reconfiguring muscle–bone crosstalk, and modulating skeletal remodeling. Furthermore, this reconfigured crosstalk influences energy metabolism, a process intrinsically linked to bone remodeling and overall musculoskeletal homeostasis. LAMB1 is identified as a pivotal mediator of integrated bone–muscle homeostasis.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157926"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linggui Zhugan Decoction mitigates post-myocardial infarction heart failure through modulation of cardiomyocyte F-actin cytoskeletal organization","authors":"Maojun Cheng ,&nbsp;Liyang Li ,&nbsp;Xing Huang ,&nbsp;Fang Ding ,&nbsp;Chengxun He ,&nbsp;Changmao Dai ,&nbsp;Jia Xu ,&nbsp;Xiangyu He ,&nbsp;Yayi Jiang ,&nbsp;Guangmin Xu ,&nbsp;Xueping Li","doi":"10.1016/j.phymed.2026.157851","DOIUrl":"10.1016/j.phymed.2026.157851","url":null,"abstract":"<div><h3>Background</h3><div>Linggui Zhugan Decoction (LGZGD), a traditional Chinese formula for spleen-strengthening and yang-warming to resolve fluid retention, has consistently shown efficacy in preventing and treating heart failure. However, its underlying biological mechanisms remain incompletely understood.</div></div><div><h3>Objective</h3><div>This study aimed to investigate the therapeutic efficacy of LGZGD in a rat model of heart failure and in H9C2 cardiomyocytes, as well as to elucidate its effects on F-actin remodeling and the underlying mechanisms.</div></div><div><h3>Methods</h3><div>A rat model of heart failure post-myocardial infarction was established by ligating the left anterior descending coronary artery, followed by treatment with LGZGD for 4 weeks. The chemical constituents of the decoction and drug-containing serum were characterized using ultra-performance liquid chromatography. Network pharmacology analysis identified potential key therapeutic targets of LGZGD for heart failure treatment. An in <em>vitro</em> hypoxia/reoxygenation injury model was constructed in H9C2 cardiomyocytes. Additionally, siRNA-mediated ROCK knockdown was performed to investigate the mechanisms underlying LGZGD–mediated regulation of F-actin remodeling in cardiomyocytes.</div></div><div><h3>Results</h3><div>The results showed that LGZGD significantly improved cardiac function and pathological morphology in heart failure rats. Network pharmacology analysis identified RhoA as a key potential target for LGZGD in regulating F-actin in heart failure. Both in <em>vivo</em> and in <em>vitro</em> experiments further confirmed that LGZGD modulates F-actin cytoskeletal remodeling.</div></div><div><h3>Conclusion</h3><div>The present findings indicate that LGZGD significantly improves cardiac function in rats with heart failure. Furthermore, it enhances the stability of F-actin cytoskeletal organization and function in both heart tissues from rats with heart failure and H9C2 cardiomyocytes.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"Article 157851"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PFKFB3-dependent endothelial-mesenchymal transition by luteolin attenuates doxorubicin-induced cardiotoxicity.","authors":"Xinyi Zhong, Yu Xia, Nan Li, Mijia Zhou, Hanyan Xie, Tianran Shi, Xiaomin Yang, Qiyan Wang, Yong Wang, Dongqing Guo","doi":"10.1016/j.phymed.2026.157945","DOIUrl":"10.1016/j.phymed.2026.157945","url":null,"abstract":"<p><strong>Background: </strong>Despite the widespread use in chemotherapy, doxorubicin (DOX) has a limited clinical use due to the associated risk of DOX-induced cardiotoxicity (DIC). Endothelial-mesenchymal transition (EndMT) has been implicated as a potential mechanism in DIC.</p><p><strong>Purpose: </strong>This study aimed to investigate the effects of luteolin on DIC and to explore its underlying mechanisms.</p><p><strong>Methods: </strong>The cardiac function and myocardial injury biomarkers were assessed in a DIC mouse model. Histological analysis was performed to evaluate myocardial structure and perivascular fibrosis. Single-nucleus RNA sequencing (snRNA-seq) of mouse heart tissue was utilized. The binding between luteolin and PFKFB3 was assessed using molecular docking and dynamics simulations. Endothelial dysfunction was assessed in human umbilical vein endothelial cells (HUVECs) by examining morphological changes, tube formation ability, migration, and collagen deposition. PFKFB3 was overexpressed in vitro to further verify the mechanism. Additionally, the anticancer activity of DOX in combination with luteolin was assessed in MCF-7 and SKBR3 cells.</p><p><strong>Results: </strong>In DIC mice, luteolin treatment noticeably improved cardiac function and reduced biomarkers related to myocardial injury. Histological analysis revealed that luteolin alleviated myocardial structural disruption and perivascular fibrosis. SnRNA-seq of mouse heart tissue identified glycolysis-related gene Pfkfb3 as a potential driver of EndMT. Molecular docking and dynamics simulations identified the formation of a stable complex between luteolin and PFKFB3. In vitro, luteolin mitigated DOX-induced endothelial dysfunction by suppressing PFKFB3-mediated EndMT pathway. Notably, PFKFB3 overexpression reversed luteolin's protection against DOX-induced injury in HUVECs. Furthermore, luteolin did not compromise the antitumor power of DOX in MCF-7 and SKBR3 cells.</p><p><strong>Conclusion: </strong>These findings indicated that luteolin ameliorated DIC by targeting PFKFB3 to inhibit EndMT. Luteolin may be a promising adjuvant therapy for mitigating DIC.</p>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"153 ","pages":"157945"},"PeriodicalIF":8.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146259105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}