Phytomedicine [JOURNAL]
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200 papers
Liquiritigenin ameliorates adipocyte insulin resistance by inhibiting pro-inflammatory polarization of macrophages via regulation of the mtROS/OXPHOS axis.
Lv C, Tan J, Ouyang H … +3 more , Zhang Z, Liu X, Zheng W
Phytomedicine · 2026 Jun · PMID 42402249 · Publisher ↗
Obesity-induced insulin resistance (IR) is closely associated with chronic inflammation and metabolic dysfunction in adipose tissue, in which macrophage polarization plays a pivotal role. Liquiritigenin (LQ), a natural f...
Obesity-induced insulin resistance (IR) is closely associated with chronic inflammation and metabolic dysfunction in adipose tissue, in which macrophage polarization plays a pivotal role. Liquiritigenin (LQ), a natural flavonoid derived from licorice, exhibits potential metabolic regulatory effects; however, its role in high-fat diet (HFD)-induced obesity and insulin resistance, as well as the underlying mechanisms, remains unclear. In this study, an HFD-induced obese mouse model combined with multi-omics analyses and an in vitro co-culture system was employed to investigate the effects of LQ. LQ significantly improved glucose tolerance, insulin sensitivity, and lipid metabolism, and restored the expression of p-IRS1/IRS1, p-AKT/AKT, and GLUT4 in epididymal adipose tissue. Integrated analyses of network pharmacology, transcriptomics, and metabolomics revealed that LQ markedly reversed HFD-induced alterations in oxidative stress, mitochondrial dysfunction, and inflammatory pathways. Mechanistically, palmitic acid (PA) at physiologically relevant concentrations did not directly induce insulin resistance in adipocytes but instead promoted macrophage polarization toward the pro-inflammatory M1 phenotype, thereby impairing adipocyte insulin signaling. Further investigation showed that PA and HFD increased mitochondrial reactive oxygen species (mtROS), disrupted oxidative phosphorylation (OXPHOS), and induced mitochondrial dysfunction in macrophages, ultimately driving M1 polarization; these effects were markedly attenuated by the mtROS scavenger Mito-TEMPO. In contrast, LQ reduced mtROS levels, restored OXPHOS function, and maintained mitochondrial homeostasis, thereby suppressing pro-inflammatory macrophage polarization and improving insulin signaling and glucose uptake in adipocytes. Notably, these effects were more pronounced than those observed with dexamethasone under the same experimental conditions. These protective effects were abolished by the mtROS activator DMNQ. In conclusion, LQ alleviates adipose tissue insulin resistance by modulating macrophage polarization through the mtROS/OXPHOS axis, providing new mechanistic insights into immunometabolic regulation and supporting of applying LQ as a potential phytotherapy strategy for obesity-related metabolic disorders.
Corrigendum to "Quercetin attenuates chondrocyte anoikis via modulation of mesenchymal stromal cell-derived small extracellular vesicles to promote cartilage repair in osteoarthritis" [Phytomedicine 146 (2025) 157146].
Cheng F, Hua H, Zhu Y … +4 more , Zhu Y, Lou P, Tong P, Zhang Y
Phytomedicine · 2026 Jul · PMID 42401520 · Publisher ↗
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Therapeutic potential of scutellarin in central nervous system: A comprehensive review.
Ma L, Chen S, Jia Q … +5 more , Tian R, Zeng Y, Luo K, Meng X, Yang L
Phytomedicine · 2026 Jun · PMID 42401072 · Publisher ↗
BACKGROUND: Scutellarin (SCU) is a flavone glycoside mainly isolated from Erigeron breviscapus (Vant.) Hand. -Mazza, which is a type of medicinal herb broadly utilized in central nervous system (CNS) disorders. Although...
BACKGROUND: Scutellarin (SCU) is a flavone glycoside mainly isolated from Erigeron breviscapus (Vant.) Hand. -Mazza, which is a type of medicinal herb broadly utilized in central nervous system (CNS) disorders. Although Scu possesses remarkable therapeutic actions on CNS disorders, the underlying mechanisms, pharmacokinetics, and safety issues are elusive. Meanwhile, the clinical trial and pharmaceutical study of SCU remain to be systematically delineated. PURPOSE: The main purpose is to comprehensively summarize the updated information regarding the pharmacological actions, clinical studies, safety issues, pharmacokinetics and novel formulations of SCU used for CNS, to point out species of interest for further studies. METHODS: The systematic search for SCU treatments for CNS disorders was performed considering all the articles published until November 2025 through multiple authoritative databases, including Web of Science, PubMed, Google Scholar, Chinese National Knowledge Infrastructure, and so on. The keywords included "scutellarin", "breviscapine", "central nervous system disorders", "ischemic stroke", "Alzheimer's disease", "pharmacokinetic", "clinical studies", and "novel preparation technology". All articles reporting the use of SCU to treat CNS disorders were retained for further analysis. RESULTS: A total of 223 articles published between 2003 and 2026 were included, covering ten CNS diseases such as ischemic stroke, Alzheimer's disease, and Parkinson's disease. Regarding pharmacological mechanisms of SCU, 33 studies focused on oxidative stress, 48 on inflammatory responses, and 16 on mitochondrial function. Evidence from 23 clinical trials indicated that SCU has therapeutic potential for CNS diseases. Toxicity studies demonstrated good safety profile at therapeutic doses of SCU. Pharmacokinetic data revealed its rapid absorption, low bioavailability, and efficient systemic clearance (16 studies). Additionally, 22 studies indicated that novel formulations significantly improved the biological half-life and enhanced the bioavailability of SCU. CONCLUSIONS: SCU is expected to become a pivotal phytochemical agent for the CNS protection. Extensive and intensive explorations on SCU are imperative to accelerate the utilization of SCU in the CNS disorders.
CHPF2-driven chondroitin sulfation of Wnt1 promotes colorectal cancer progression and is targeted by ponicidin.
Ye Y, Liang Y, Lan H … +5 more , Zhang N, Ke Y, An L, Liu Z, Wang C
Phytomedicine · 2026 Jun · PMID 42401071 · Publisher ↗
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death worldwide, mainly due to cancer cell proliferation and migration. Although chondroitin sulfate (CS) is involved in cancer progression, its regulatory...
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death worldwide, mainly due to cancer cell proliferation and migration. Although chondroitin sulfate (CS) is involved in cancer progression, its regulatory mechanisms remain unclear. PURPOSE: To investigate the role and mechanism of chondroitin polymerizing factor 2 (CHPF2) and CS in CRC progression, as well as to evaluate the therapeutic potential of ponicidin. METHODS: The correlation between CHPF2 and prognosis was analyzed in clinical samples. Mechanistically, ponicidin was found to target CHPF2, suppress CS synthesis, and consequently block the Wnt/β-catenin pathway. Its anti-tumor efficacy was validated in cellular, organoid, and animal models. RESULTS: We identified CHPF2, a key enzyme in CS synthesis, as a critical driver of CRC. CHPF2 is significantly overexpressed in CRC tissues, and its high expression correlates with advanced disease stage and poor patient prognosis. Functionally, CHPF2 drives tumor cell proliferation, migration, and survival by enhancing CS production. Mechanistically, CS promotes the activation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT). This effect is associated with CS-dependent modifications of Wnt1; however, further investigation is required to determine whether Wnt1 is directly modified by CS chains or indirectly affected via CS-modified proteoglycans. Furthermore, the natural diterpenoid ponicidin derived from Rabdosia rubescens directly targets CHPF2 and inhibits its enzymatic activity, thereby reducing CS biosynthesis and subsequently blocking the Wnt/β-catenin signaling pathway. The anti-tumor efficacy of ponicidin was validated in cellular models, patient-derived organoids, and primary CRC models, demonstrating its potent inhibitory effects on tumor growth and metastasis. CONCLUSION: Our study reveals the oncogenic role of the CHPF2/CS axis in CRC, establishes CHPF2 as a novel therapeutic target, and provides compelling preclinical evidence supporting ponicidin as a promising CHPF2-targeted agent for CRC treatment.
Xuefu Zhuyu Decoction Ameliorates Neuroinflammation after Traumatic Brain Injury via tRF-3-Leu-AAG/Gpr17 axis.
Yang Z, Yuan Z, Hou J … +8 more , Long Y, Luo M, Lai Z, Zhong Z, Fan X, Chen D, Tang T, Wang Y
Phytomedicine · 2026 Jun · PMID 42401070 · Publisher ↗
BACKGROUND: Xuefu Zhuyu Decoction (XFZYD) is clinically applied to traumatic brain injury (TBI) based on its traditional function of activating blood circulation and eliminating stasis. However, its precise mechanism und...
BACKGROUND: Xuefu Zhuyu Decoction (XFZYD) is clinically applied to traumatic brain injury (TBI) based on its traditional function of activating blood circulation and eliminating stasis. However, its precise mechanism underlying its efficacy, particularly through epigenetic regulation, are poorly understood. AIM OF THE STUDY: We hypothesized that the neuroprotective effects of XFZYD post-TBI are mediated through the modulation of transfer RNA-derived small RNAs (tsRNAs), a key class of epigenetic regulators. This study aimed to delineate the specific tsRNA-dependent molecular pathway underlying XFZYD's ability to mitigate neuroinflammation and facilitate neurological recovery. MATERIALS AND METHODS: We employed a murine TBI model treated with XFZYD. Following comprehensive assessment of neurological, histopathological, and inflammatory outcomes to test the mice behavior. The anti-infammatory roles of tRF-3-Leu-AAG was investigated in vivo and in vitro. RNA sequencing and bioinformatics analysis revealed G protein-coupled receptor 17 (Gpr17) is tRF-3-Leu-AAG's target. The direct interaction between tRF-3-Leu-AAG and Gpr17 is validated by dual-luciferase assay. Finally, in vitro rescue experiments conclusively established the tRF-3-Leu-AAG/Gpr17 axis as the functional pathway underlying XFZYD's effects. RESULTS: XFZYD administration significantly attenuated neurological deficits, neuronal loss, and rescued cognitive impairment post-TBI. tRF-3-Leu-AAG, as a crucial mediator, which is suppressed by TBI and upregulated by XFZYD. The study demonstrated that tRF-3-Leu-AAG affect the inflammatory response. Critically, the anti-inflammatory and neuroprotective effects of XFZYD were entirely dependent on tRF-3-Leu-AAG. We further delineated the downstream signaling by identifying Gpr17 as a direct and functional target of tRF-3-Leu-AAG. XFZYD mediated tRF-3-Leu-AAG binds to the 3'UTR of Gpr17 mRNA to suppress its expression, thereby inhibiting the Gpr17-induced pro-inflammatory pathway. CONCLUSION: This study elucidates that XFZYD exerts neuroprotection and anti-inflammation after TBI through tRF-3-Leu-AAG/Gpr17 axis. Our findings provide a modern scientific rationale for the application of XFZYD in treating TBI.
Fangchinoline alleviates atypical hyperplasia of metaplastic ducts and pancreatic fibrosis in caerulein-induced mice.
Du X, Cai Y, Zhang L … +12 more , Ji M, Sun Y, Ye A, Zhang H, Mo Q, Wang Z, Wang M, Li Y, Li T, Tang C, Ma J, Li Y
Phytomedicine · 2026 Jul · PMID 42401069 · Publisher ↗
BACKGROUND: Chronic pancreatitis (CP) is a progressive fibro-inflammatory disease in which acinar-to-ductal metaplasia (ADM) and fibrosis form a vicious cycle, representing an early event in pancreatic carcinogenesis. Fa...
BACKGROUND: Chronic pancreatitis (CP) is a progressive fibro-inflammatory disease in which acinar-to-ductal metaplasia (ADM) and fibrosis form a vicious cycle, representing an early event in pancreatic carcinogenesis. Fangchinoline, a bisbenzylisoquinoline alkaloid from Stephania tetrandra, exhibits anti-inflammatory and anti-fibrotic properties, although its role in ADM-fibrotic lesions remains unknown yet. OBJECTIVE: To investigate the effects of fangchinoline on atypical hyperplasia of metaplastic ducts and pancreatic fibrosis, and to clarify its underlying mechanisms. METHODS: Network pharmacology, bioinformatics, molecular docking, dynamics simulations, and cellular assays were used to elucidate and verify the underlying mechanisms. A C57BL/6 J mouse model was used to elucidate the effects, hepatotoxicity, nephrotoxicity, and cardiotoxicity of fangchinoline. RESULTS: Fangchinoline alleviated caerulein-induced atypical hyperplasia of metaplastic ducts (64.3%) and reduced pancreatic fibrosis (70.8%). In terms of molecular mechanisms, it targeted bound to the kinase domains of proto-oncogene tyrosine-protein kinase SRC (SRC) and receptor tyrosine-protein kinase ERBB-2 (ERBB2), suppressed their phosphorylation, blocked the downstream focal adhesion kinase (FAK)/zinc finger E-box binding homeobox 1 (ZEB1) signalling, reversed epithelial-mesenchymal transition (EMT), attenuated cancer stemness properties, and reduced the secretion of pro-fibrotic factors. These actions disrupted the vicious cycle between ADM and fibrosis. CONCLUSION: Fangchinoline is a promising multi-target therapeutic candidate for atypical hyperplasia of metaplastic ducts and pancreatic fibrosis.
Dihydroberberine regulates the ferroptosis-autophagy positive feedback loop in colorectal cancer by targeting PANX2.
Xu L, Meng Q, Wang F … +5 more , Mi Y, Jia Y, Lei N, He D, Hou Y
Phytomedicine · 2026 Jul · PMID 42401068 · Publisher ↗
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide and remains a major clinical challenge, underscoring the urgent need for novel therapeutic targets and treatment strategies. Ferroptosi...
BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies worldwide and remains a major clinical challenge, underscoring the urgent need for novel therapeutic targets and treatment strategies. Ferroptosis, a form of cell death triggered by iron-dependent lipid peroxidation, is emerging as a promising new anti-cancer therapeutic strategy. PURPOSE: This study aims to identify a key target regulating the ferroptosis process in CRC, screen for small molecule modulators against this target, and elucidate their potential anti-tumor mechanisms. METHODS: We developed a Drug Discovery Strategy for Targeted Ferroptosis Therapy Based on Bioinformatics-Machine Learning Integration for the Treatment of CRC (DDTF-BMLI-CRC), aiming to identify key ferroptosis regulators. The functional role of this factor in CRC and ferroptosis was validated through knockdown and overexpression techniques, establishing it as a potential therapeutic target. Subsequently, candidate compounds were screened from natural product and FDA databases using a dual-scoring model combining machine learning and deep learning. The direct binding of candidate compounds to target proteins was validated through molecular docking, molecular dynamics simulations, DARTS, CETSA, and SPR techniques. Finally, a series of in vitro and in vivo experiments were conducted to systematically evaluate their anti-tumor effects and potential mechanisms. RESULTS: PANX2 was identified as a key ferroptosis-suppressing gene in CRC. We discovered the natural small molecule dihydroberberine (dhBBR) to be a potent and direct inhibitor of the PANX2 protein. In vitro, dhBBR significantly inhibited the proliferation, migration, and invasion of CRC cells while inducing ferroptosis. In vivo, dhBBR effectively suppressed xenograft tumor growth. Mechanistic studies revealed that dhBBR-induced ferroptotic stress activates autophagy, which in turn promotes GPX4 degradation, thereby amplifying the ferroptotic effect and establishing a ferroptosis-autophagy positive feedback loop. Crucially, PANX2 knockdown largely abolished the additional anti-tumor effect of dhBBR, and dhBBR did not further suppress tumor growth beyond PANX2 knockdown alone. CONCLUSION: This study demonstrates that PANX2 knockdown suppresses CRC progression by inducing ferroptosis. Furthermore, we identified dhBBR for the first time as a PANX2-targeting small-molecule inhibitor. Our research reveals a novel therapeutic strategy targeting the PANX2-mediated ferroptosis-autophagy axis and provides a highly promising candidate compound for the treatment of CRC.
Run Chang Tong Mi tea alleviates functional constipation through regulating gut microbiota and SCF/c-kit pathway.
Zhang C, Jiang Y, Li X … +5 more , Wan Z, Li M, Xu Q, Wang W, Huo J
Phytomedicine · 2026 Jun · PMID 42398209 · Publisher ↗
BACKGROUND: Functional constipation (FC) is a gastrointestinal motility disorder related to intestinal transit function and hormonal imbalance and has been reported to be associated with an imbalance in the gut microbiot...
BACKGROUND: Functional constipation (FC) is a gastrointestinal motility disorder related to intestinal transit function and hormonal imbalance and has been reported to be associated with an imbalance in the gut microbiota. Clinically, Run Chang Tong Mi tea (RCTM) can effectively alleviate the constipation symptoms of patients with FC. However, the mechanism by which RCTM improves FC and its regulation of intestinal homeostasis remain unclear. PURPOSE: This study aims to investigate the potential mechanism of RCTM alleviates FC by improving intestinal motility and mucosal secretion function through gut microbiota and its metabolites. METHOD: The FC rat model was established by loperamide hydrochloride. The treatment effect of RCTM was evaluated by assessing stool frequency, fecal water content, time to first black stool, and small bowel transit rate. The histological changes of colon were observed by HE staining. Serum and colonic hormone levels were measured by ELISA. Immunohistochemistry was performed to assess the expression of tight junction proteins associated with the intestinal barrier. Western blotting and RT-qPCR were used to analyze the expression of SCF/c-kit pathway and intestinal barrier related proteins and mRNA, 16S rDNA sequencing was used to analyze the composition of intestinal microbiota, and GC/MS was used to detect SCFAs levels. By transplanting RCTM-treated fecal bacteria into FC rats, the relationship between the disturbance of gut microbiota, the onset of FC and the effect of RCTM intervention was further clarified. RESULTS: RCTM can effectively restore the gastrointestinal motility and repair the damaged intestinal barrier in FC rats. RCTM promoted the secretion of excitatory hormones and neurotransmitters in the gastrointestinal tract, and regulated the mRNA and protein content of SCF/c-kit pathway. Furthermore, RCTM restored gut microbiota disorder and SCFAs content. More importantly, RCTM-FMT effectively alleviated constipation symptoms and increased gastrointestinal hormone and neurotransmitter levels, effects that were associated with alterations in the abundance of Lachnospiraceae and Lactobacillus as well as enhanced SCFA production. Moreover, RCTM-FMT improved intestinal barrier function, which was associated with decreased abundances of Escherichia-Shigella and Dubosiella. CONCLUSION: Our findings indicate that RCTM alleviated constipation in rats with FC, and this amelioration was associated with modulation of the gut microbiota, elevation of SCFAs, and restoration of the SCF/c-kit pathway.
Abrus cantoniensis α-glucan-like polysaccharide alleviates influenza via gut microbial acetate to activate free fatty acid receptor 2/ mitochondrial antiviral signaling protein/interferon-beta pathway.
Yi Y, Li D, Li Y … +8 more , Wang H, Yang D, Yang S, Xing S, Wei S, Yang J, Guo H, Luo Z
Phytomedicine · 2026 Jun · PMID 42398208 · Publisher ↗
BACKGROUND: The gut microbiota is critical for host defense against influenza. Polysaccharides are known for their microbiota-modulating and immunomodulatory activities; however, the anti-influenza efficacy of homogeneou...
BACKGROUND: The gut microbiota is critical for host defense against influenza. Polysaccharides are known for their microbiota-modulating and immunomodulatory activities; however, the anti-influenza efficacy of homogeneous Abrus cantoniensis polysaccharides (ACP) remains unexplored. PURPOSE: The present study seeks to clarify the protective role of ACP in influenza and explore its underlying molecular mechanisms. METHODS: Initially, crude polysaccharides were extracted via ethanol precipitation and subsequently purified by gel chromatography. Systematic structural characterization of ACP was then performed using carbohydrate chemistry techniques, including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), ultraviolet (UV) spectroscopy, and nuclear magnetic resonance (NMR). The therapeutic efficacy of ACP was assessed by monitoring various indicators such as body weight, survival rate, viral load, and pulmonary pathological changes in mouse models. Furthermore, to elucidate the biological mechanism underlying ACP's anti-influenza activity via regulation of pulmonary interferon-beta (IFN-β) immune networks by intestinal acetate-producing microbiota, multi-omics analyses integrating metagenomics, metabolomics, gene knockout, immunofluorescence, and Western blot were conducted. Finally, the potential anti-influenza effects of ACP via the gut-lung axis were evaluated based on in vivo and in vitro detection of protein expression of IFN-β, free fatty acid receptor 2 (FFAR2), and mitochondrial antiviral signaling protein (MAVS), as well as antiviral interferon-stimulated genes (ISGs). RESULTS: In this study, we purified a novel polysaccharide, ACP-A1, with a backbone of→4)-α-D-Glcp-(1→,→4)-β-D-Galp-(1→, and →4,6)-α-D-Glcp-(1→ linkages and α-D-Glcp-(1→ branches at O-6. In H1N1-infected mice, oral ACP-A1 alleviated weight loss, increased survival, and reduced lung inflammation and viral load. Metagenomic and targeted metabolomic analyses showed that ACP-A1 enriched Limosilactobacillus reuteri and elevated acetate levels. Fecal microbiota transplantation, FFAR2 inhibition, and MAVS knockout experiments demonstrated that ACP-A1 enhances the FFAR2/MAVS/IFN-β antiviral pathway via microbial-derived acetate. CONCLUSION: Collectively, our findings elucidate that ACP mitigates influenza virus-induced lung dysfunction by promoting the proliferation of acetate-producing gut microbiota, particularly Limosilactobacillus reuteri, and activating the FFAR2/MAVS/IFN-β antiviral axis in pulmonary immune cells. These findings establish ACP-A1 as a natural polysaccharide regulating IFN-β homeostasis, highlighting its potential for influenza prevention.
Kaempferitrin attenuates DSS-induced colitis by promoting ubiquitination-mediated degradation of the nuclear factor kappa B p65.
Cheng J, Ren K, Wang L … +4 more , Shi Y, Kuang T, Fu S, Pan S
Phytomedicine · 2026 Jun · PMID 42398207 · Publisher ↗
BACKGROUND: Inflammatory bowel disease (IBD), including colitis, is commonly associated with dysfunction of the intestinal barrier and inflammatory responses. Current medications used to treat IBD may cause severe side e...
BACKGROUND: Inflammatory bowel disease (IBD), including colitis, is commonly associated with dysfunction of the intestinal barrier and inflammatory responses. Current medications used to treat IBD may cause severe side effects with long-term use. Previous studies have confirmed that Bupleuri Radix extract exhibits significant anti-inflammatory effects. However, the therapeutic effects of its active component, kaempferitrin (KPN), on dextran sulfate sodium (DSS)-induced colitis in mice and the underlying mechanisms remain largely unexplored. PURPOSE: The aim of this study was to investigate the therapeutic effects of KPN on colitis in mice and explore its potential mechanisms. METHODS: This study employed a DSS-induced colitis mouse model to evaluate KPN's therapeutic effects. Mice were divided into control, model, 5-Aminosalicylic Acid (5-ASA), and KPN treatment groups, followed by DAI, histopathology, inflammatory cytokines, gut barrier proteins, and gene expression. RESULTS: This investigation revealed that Kaempferitrin (KPN), an active constituent within Bupleuri Radix extract, attenuates pathological manifestations, inflammatory cascades, and barrier dysfunction in dextran sulfate sodium (DSS)-induced murine colitis. Integrative network pharmacology and transcriptomic analyses identify NDRG2 as a potential target of KPN in the treatment of colitis. Co-immunoprecipitation (Co-IP) and mass spectrometry showed that KPN enhanced the interaction between NDRG2 and NF-κB p65, whereas mechanistic studies in bone marrow-derived macrophages (BMDMs), supported by public single-cell RNA-seq analysis and NDRG2/F4/80 co-localization in inflamed colon tissues, indicated that macrophages represent a relevant cellular context for the KPNNDRG2-p65 axis. Through the utilization of a biotin-conjugated KPN probe, direct molecular interaction between KPN and NDRG2 was established, with site-directed mutagenesis revealing E164, P280, and M314 as critical amino acid residues mediating this interaction. Mechanistically, KPN promoted NDRG2-associated recruitment of FBXO11, facilitating K48-linked ubiquitination and proteasomal degradation of p65 in BMDMs, thereby suppressing NF-κB activation and inflammatory cytokine expression. Additionally, in vivo experimental evidence indicated that NDRG2 ablation (NDRG2) substantially diminished the protective efficacy of KPN against DSS-induced colitis and compromised its capacity to inhibit p65. CONCLUSION: KPN directly engages NDRG2 and modulates a BMDMs-associated NDRG2-FBXO11-p65 axis to restrain NF-κB signaling, providing mechanistic insight into the anti-inflammatory effects of KPN in experimental colitis.
Unveiling the pharmacological basis of Rhodiola crenulata for atopic dermatitis: A multi-model approach combining zebrafish, mouse studies, and intelligent computational analysis.
Zhang X, Wang Y, Zhao D … +10 more , Yin C, Wu H, Zeng J, Shi X, He M, Feng G, Wang Y, Liu J, Huang W, Tian H
Phytomedicine · 2026 Jun · PMID 42398206 · Publisher ↗
BACKGROUND: Atopic dermatitis (AD) is a complex inflammatory skin disorder. Rhodiola crenulata extract (RC) contains bioactive compounds with potential benefits for AD, but its mechanisms are not fully elucidated. METHOD...
BACKGROUND: Atopic dermatitis (AD) is a complex inflammatory skin disorder. Rhodiola crenulata extract (RC) contains bioactive compounds with potential benefits for AD, but its mechanisms are not fully elucidated. METHODS: A DNCB-induced AD mouse model and zebrafish models were used to evaluate efficacy and multi-dimensional activities. RC was separated into microfractions by preparative liquid chromatography. An OPLS-DA model, based on zebrafish bioactivity and LC-MS profiling, predicted active compounds, which were validated. Mechanisms were investigated via transcriptome sequencing, Western blot, qPCR, network pharmacology, and molecular docking. RESULTS: RC alleviated AD-like symptoms in mice, reducing epidermal thickening, mast cell infiltration, and splenomegaly. Four active monomers were identified, with kaempferol and naringenin showing the most prominent anti-inflammatory and analgesic effects, while salidroside exhibited strong antioxidant activity. RC and its active components primarily inhibited the NLRP3/Caspase-1/IL-1β axis, while also modulating oxidative stress (e.g., NOX2, PRDX2), cAMP/PKA signaling, and skin barrier-repair pathways. Network pharmacology and molecular docking confirmed efficient binding of four core compounds to NLRP3, CASP1, and IL-1B. CONCLUSION: This study demonstrates that RC alleviates AD by inhibiting the NLRP3 inflammasome pathway, identifying kaempferol, naringenin, salidroside and rhodiosin as key constituents, providing a foundation for developing RC as a natural AD therapeutic.
Kuntai capsule ameliorates PCOS by reversing tryptophan metabolic shift and aberrant nuclear AHR activation: a multi-omics investigation.
Hu R, Li F, Dong H … +11 more , Zhang L, Xiong L, Wang F, Liu Z, Huang Y, Zhang Z, Wang X, Liu C, Song K, Song Y, Zhang M
Phytomedicine · 2026 Jun · PMID 42398205 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) represents a multifaceted reproductive endocrine disorder with growing evidence linking its pathogenesis to metabolic alterations. In particular, dysregulation of the tryptoph...
BACKGROUND: Polycystic ovary syndrome (PCOS) represents a multifaceted reproductive endocrine disorder with growing evidence linking its pathogenesis to metabolic alterations. In particular, dysregulation of the tryptophan-kynurenine metabolism has emerged as a key contributor, though the precise mechanisms involved remain poorly defined. Kuntai Capsule (KT) has shown potential in managing obese PCOS, yet its role in modulating tryptophan metabolism warrants further investigation. PURPOSE: To define the contribution of tryptophan metabolic shift to PCOS and to evaluate the therapeutic potential of KT. METHODS: An obese PCOS rat model was developed with testosterone propionate and high-fat diet. The efficacy of KT was assessed by tracking changes in weight, glycolipid metabolism, estrous cycle, ovarian morphology, and serum sex hormone levels. Additionally, multi-omics analyses and WB were integrated to investigate alterations in the tryptophan-kynurenine metabolism in serum and multiple target organs. The distribution of the kynurenine ligand, the AHR in the cytoplasm and nucleus, as well as changes in its downstream molecules, were investigated to elucidate the role of tryptophan metabolism-kynurenine pathway-AHR signaling axis in the mechanism underlying the metabolic and reproductive comorbidities of PCOS and the effect of KT. An in vitro model was established by treating KGN cells with L-kynurenine. The expression levels of AHR, CYP1B1, and CX43 in KGN cells were analyzed. Finally, confirmatory studies were performed using AHR agonist and antagonist. RESULTS: KT effectively attenuated the disturbed glycolipid metabolism, disrupted estrous cycle, altered sex hormone levels, and aberrant ovarian morphology in PCOS rats. Mechanistically, the model rats exhibited overactivated IDO1 and TDO2 and disrupted gut microbiota homeostasis, inducing a marked shift in tryptophan metabolism toward the kynurenine pathway. It resulted in the accumulation of kynurenine in the circulation and tissues. This kynurenine accumulation further drove aberrant nuclear AHR accumulation, which was associated with upregulation of CYP1B1 and CD36 expression in the liver, and upregulation of CYP1B1 accompanied by downregulation of the CX43 along with enhanced phosphorylation of CX43 in the ovaries. These key molecular alterations were effectively reversed by KT intervention. In vitro experiment further confirmed that KT directly antagonized kynurenine-induced excessive nuclear accumulation of AHR and elevated expression of CYP1B1. CONCLUSIONS: Overactivated IDO1 and TDO2, together with disrupted gut microbiota homeostasis, induced tryptophan metabolism shift, which overactivated nuclear AHR accumulation. It was linked to hepatic steatosis and insulin resistance via CYP1B1 and CD36 upregulation, and was also associated with disrupted ovarian function through altered CYP1B1 and CX43 expression. KT restored tryptophan metabolism and curtailed the exorbitant expression of nuclear AHR, ameliorating both metabolic and reproductive disorders in PCOS.
Corrigendum to "Bushentongluo formula counteracts BMSCs senescence to alleviate postmenopausal osteoporosis by activating mitophagy via the SENP1-SIRT3 pathway" [Phytomedicine 152 (2026) 157827].
Chen S, Yu L, Tian N … +8 more , Zhao Q, Qin M, Shao L, Sun P, Ma P, Wang J, Fang P, Min W
Phytomedicine · 2026 Jul · PMID 42392876 · Publisher ↗
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Palmatine restores airway epithelial barrier function of asthma by inhibiting Alox15-mediated ferroptosis.
Zhao L, Wu J, Zhang Y … +4 more , Zhao Y, Lin Y, Zhang M, Bao W
Phytomedicine · 2026 Jun · PMID 42391816 · Publisher ↗
BACKGROUND: Epithelial barrier dysfunction plays a key role in asthma pathogenesis. Palmatine has been shown to reinforce epithelial integrity in colitis and ameliorate urticaria-like skin inflammation, suggesting potent...
BACKGROUND: Epithelial barrier dysfunction plays a key role in asthma pathogenesis. Palmatine has been shown to reinforce epithelial integrity in colitis and ameliorate urticaria-like skin inflammation, suggesting potential barrier-protective effects. PURPOSE: To investigate the barrier-protective role of palmatine in eosinophilic asthma. STUDY DESIGN AND METHODS: An ovalbumin-induced eosinophilic asthma model was established. After palmatine administration, lung function, airway responsiveness, mucus secretion, collagen deposition, and epithelial barrier integrity were assessed. Proteomics, molecular docking, cellular experiments, and immunofluorescence were performed to elucidate underlying mechanisms. RESULTS: Palmatine markedly restored epithelial barrier integrity by upregulating E-cadherin, occludin, and ZO-1. Correspondingly, it improved both large- and small-airway obstruction, and reduced airway hyperresponsiveness. It also reduced IL-5, IL-13, and MMP9 levels, indicating attenuation of inflammation and collagen deposition. Proteomics and mechanistic studies revealed that palmatine suppressed Alox15-mediated ferroptosis in airway epithelial cells, reflected by reduced GSSG, MDA, and LPO and increased GSH levels in lung tissue. In erastin-treated BEAS-2B cells, palmatine inhibited Alox15 and PEBP1 expression accompanied by recovery of epithelial junction proteins E-cadherin, occludin, and ZO-1. CONCLUSION: Palmatine exhibits therapeutic effects in eosinophilic asthma. By inhibiting Alox15-mediated ferroptosis, it restores airway epithelial barrier integrity and alleviates inflammation and airway hyperresponsiveness, highlighting its promise as a potential therapeutic agent for eosinophilic asthma.
Menaquinone-7 preserves Prg4 chondrocytes from iron-driven damage in aging associated osteoarthritis by targeting GPR68/MAPK/GPX4 feed-forward loop.
He Q, Chen B, Zeng J … +8 more , Pan Z, Wang F, Wang X, Li M, Ye P, He J, Zhou C, Wang H
Phytomedicine · 2026 Jun · PMID 42391815 · Publisher ↗
BACKGROUND: Aging-associated knee osteoarthritis (KOA) is a degenerative joint disease with limited disease-modifying treatment options. Increasing evidence suggests that iron accumulation in aging joints drives oxidativ...
BACKGROUND: Aging-associated knee osteoarthritis (KOA) is a degenerative joint disease with limited disease-modifying treatment options. Increasing evidence suggests that iron accumulation in aging joints drives oxidative stress and lipid peroxidation, potentially contributing to cartilage degeneration through ferroptosis. However, the cellular targets and molecular mechanisms underlying iron-driven ferroptotic injury in articular cartilage remain largely unclear. PURPOSE: This study aimed to investigate whether menaquinone-7 (MK-7) acts as a mechanism-based intervention targeting GPR68 to protect Prg4⁺ chondrocytes from iron-driven ferroptosis and to define the underlying signaling mechanisms in aging-associated KOA. METHODS: Clinical cartilage and synovial samples were analyzed to characterize iron accumulation and redox alterations in aging-associated KOA. Synovial metabolomic profiling was performed to identify changes in iron-related metabolic pathways. To investigate the underlying mechanisms, in vivo and ex vivo osteoarthritis models, including murine and equine systems, were established to examine ferroptosis-related changes in Prg4⁺ chondrocytes using histological, biochemical, and imaging-based analyses. GPR68 knockout mice were employed to determine the role of GPR68 in mediating iron-driven ferroptosis. Subsequently, in vitro experiments were conducted to evaluate the effects of MK-7 on iron-induced ferroptosis in chondrocytes. Molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to assess the interaction between MK-7 and GPR68. Downstream signaling analyses were performed to elucidate the involvement of the GPR68/MAPK/GPX4 axis. RESULTS: Clinical analyses and synovial metabolomic profiling revealed that aging-associated osteoarthritic joints exhibited marked iron accumulation accompanied by depletion of vitamin K2-related metabolites, suggesting profound redox remodeling in the joint microenvironment. Iron overload was preferentially associated with ferroptosis-like injury in Prg4⁺ superficial chondrocytes, characterized by enhanced lipid peroxidation, impaired GPX4-dependent antioxidant defense, and early extracellular matrix (ECM) damage. Mechanistically, iron overload selectively activated GPR68 and triggered a pathological MAPK/GPX4 feed-forward loop that amplified ferroptotic vulnerability in Prg4⁺ chondrocytes. Genetic ablation of GPR68 attenuated iron-driven ferroptotic injury and alleviated cartilage degeneration, confirming its critical role in this process. Among vitamin K2 isoforms, MK-7 directly bound to GPR68, restored GPX4-dependent redox homeostasis, and suppressed MAPK hyperactivation under iron overload. In vivo and ex vivo murine and equine models further demonstrated that intra-articular MK-7 administration reduced chondrocyte ferroptosis, preserved ECM integrity, and attenuated osteoarthritic progression. CONCLUSION: This study identifies iron-driven ferroptotic stress in Prg4⁺ superficial chondrocytes as a key pathological feature of aging-associated osteoarthritis. We demonstrate that GPR68 functions as a critical sensor linking iron-induced microenvironmental alterations to MAPK activation and GPX4-dependent redox imbalance, thereby promoting ferroptosis-associated cartilage degeneration. Importantly, we further show that MK-7 directly targets GPR68 to restore redox homeostasis, suppress ferroptotic injury, and preserve cartilage integrity in both in vivo and ex vivo models. These findings not only provide mechanistic insights into the role of iron-driven ferroptosis in osteoarthritis progression but also highlight MK-7 as a promising mechanism-based therapeutic candidate for disease modification in aging-associated KOA.
Gigantol induces ferroptosis in gastric cancer via methyltransferase-like 3/YTH domain-containing family protein 2-mediated β-catenin degradation.
Wang C, Zhao D, Jiang H … +5 more , Zhang N, Wang Y, Ni J, Zhao Q, Hu A
Phytomedicine · 2026 Jun · PMID 42391814 · Publisher ↗
BACKGROUND: Gastric cancer (GC) poses a significant therapeutic challenge worldwide, highlighting an urgent need for novel and effective treatment strategies. Recently, natural compounds targeting ferroptosis have emerge...
BACKGROUND: Gastric cancer (GC) poses a significant therapeutic challenge worldwide, highlighting an urgent need for novel and effective treatment strategies. Recently, natural compounds targeting ferroptosis have emerged as promising candidates in the management of GC. Gigantol is a natural bibenzyl compound extracted from the Dendrobium genus, a traditional Chinese medicinal plant used for centuries to treat various gastric disorders. However, the anti-tumor effects of gigantol on GC and the underlying mechanisms remain largely unexplored. PURPOSE: This study aimed to investigate the anti-tumor effects of gigantol on GC, elucidate the underlying mechanisms, and explore its combined effects with apatinib. METHODS: CCK-8, colony formation, transwell, DCFH-DA staining, and ELISA assays were performed to evaluate the anti-tumor effects of gigantol on GC in vitro. Mechanistic explorations were conducted via MeRIP-qPCR, RIP-qPCR, Western blot, cell transfection, and RNA stability assays. Cell-derived xenograft and tail vein-lung metastatic models were utilized to evaluate the efficacy of gigantol in vivo. RESULTS: Gigantol significantly inhibited the proliferation and metastasis of GC cells, which may be associated with the induction of ferroptosis. Mechanistically, gigantol increased mA levels on β-catenin mRNA by promoting METTL3. Then, YTHDF2 was recruited to facilitate the degradation of β-catenin mRNA. The consequent depletion of β-catenin led to the downregulation of GPX4, which in turn triggered ferroptosis, ultimately inhibiting GC progression. Furthermore, the combination of gigantol and apatinib potentiated anti-tumor efficacy, likely through enhanced induction of ferroptosis. CONCLUSION: This study suggests that gigantol exerts anti-tumor effects on GC, at least in part, by inducing ferroptosis via the METTL3/mA/β-catenin/GPX4 pathway, providing a potential therapeutic strategy for GC patients.
Corrigendum to "Diosgenin as a substitute for cholesterol alleviates NAFLD by affecting CYP7A1 and NPC1L1-related pathway" [Phytomedicine, 125 (2024), 155299].
Yan M, Man S, Dai Y … +3 more , Zhao Y, Ma L, Gao W
Phytomedicine · 2026 Jul · PMID 42385434 · Publisher ↗
Abstract loading — click title to view on PubMed.
Daphnetin alleviates influenza pneumonia by enhancing chaperone-mediated autophagy of KEAP1 through Heat shock cognate 71 kDa protein.
Wang J, Liu H, Pan X … +7 more , Liu T, Li Q, Yuan Y, Zhang J, Zhao S, Yan X, Su J
Phytomedicine · 2026 Jun · PMID 42385433 · Publisher ↗
BACKGROUND: Inflammatory injury due to viral pneumonia (e.g., influenza A virus [IAV]) is a major cause of death in severe respiratory diseases. Daphnetin, a natural coumarin, has therapeutic potential against viral pneu...
BACKGROUND: Inflammatory injury due to viral pneumonia (e.g., influenza A virus [IAV]) is a major cause of death in severe respiratory diseases. Daphnetin, a natural coumarin, has therapeutic potential against viral pneumonia; however, its direct target and mechanism of action remain unclear. PURPOSE: Experimental study on the therapeutic effect and mechanism of daphnetin in viral pneumonia. METHODS: We integrated limited proteolysis-mass spectrometry, surface plasmon resonance, and molecular docking with cellular experiments and murine IAV models. Target validation was performed via siRNA knockdown and pathway inhibitors. Molecular expression and signaling were assessed using flow cytometry and western blotting. RESULTS: Daphnetin directly bound to Heat shock cognate 71 kDa protein (HSC70), enhancing its interaction with kelch-like ECH-associated protein 1 (KEAP1) to activate chaperone-mediated autophagy (CMA) and KEAP1 lysosomal degradation, thereby sustaining Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) antioxidant pathway activation. This mitigated mitochondrial oxidative stress and mitochondrial DNA (mtDNA) leakage, inhibited cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) inflammation, restored macrophage efferocytosis, and reduced pulmonary inflammatory injury in mice. CONCLUSION: This study identified the HSC70-CMA-NRF2 axis as the key mechanism underlying the modulation of macrophage function by daphnetin, providing a theoretical basis for its development as a targeted immunometabolic regulator of viral pneumonia.
Polyphenols extracted from Lycium barbarum seeds regulate gut microbiota to improve type 2 diabetes mellitus in db/db mice.
Zhang J, Gong R, Liu Y … +3 more , Deng J, Wang J, Yang H
Phytomedicine · 2026 Jun · PMID 42385432 · Publisher ↗
BACKGROUND: Mounting evidence positions the gut microbiota as a pivotal player in the onset and progression of type 2 diabetes mellitus (T2DM). Lycium barbarum seed polyphenols (LBSPs), a byproduct of Lycium barbarum pro...
BACKGROUND: Mounting evidence positions the gut microbiota as a pivotal player in the onset and progression of type 2 diabetes mellitus (T2DM). Lycium barbarum seed polyphenols (LBSPs), a byproduct of Lycium barbarum processing, have shown antioxidant and anti-inflammatory bioactivities, but potential anti-T2DM effects remain unclear. PURPOSE: To evaluate the preventive effects of LBSPs against T2DM and the associated gut microbiota mechanisms. METHODS: The effects of LBSPs on fasting blood glucose, insulin sensitivity, liver lipid accumulation, intestinal barrier, gut microbiota composition, and microbial metabolites were investigated in db/db mice. RESULTS: LBSPs significantly reduced fasting blood glucose, improved insulin sensitivity, and alleviated dyslipidemia and hepatic steatosis in db/db mice. Furthermore, LBSPs restored intestinal barrier integrity by up-regulating tight junction proteins Claudin-1, Occludin, and Zonula Occludens-1 (ZO-1). 16S rRNA analysis revealed that LBSPs reversed gut microbiota dysbiosis, enriching Lactobacillus, Ligilactobacillus, Rikenella, Lachnospiraceae_NK4A136_group, while decreasing Escherichia-Shigella and Klebsiella. Mechanically, LBSPs can modulate aromatic amino acid metabolism, lipid metabolism, and bile acid biosynthesis by metabolomics. Mediation analysis indicated that specific gut microbiota influenced host metabolic parameters through metabolites such as 7-megastigmene-3,6,9-triol 9-glucoside. CONCLUSION: Our findings reveal that LBSPs can be used as a potential microbiota-targeted nutraceutical that reverses gut microbiota dysbiosis and diabetes-associated metabolic disorders during T2DM progression.
Shemazhichuan liquid alleviates airway remodeling by modulating mitochondrial dysfunction via the EIF4E/HIF-1α/ROS pathway.
Zhang M, Wang T, Rao L … +8 more , Huang H, Liao G, Liang H, Peng X, Luo Z, Jiang Y, Zhan S, Huang X
Phytomedicine · 2026 Jun · PMID 42385431 · Publisher ↗
BACKGROUND: Airway remodeling is a pivotal pathological driver of asthma progression. Shemazhichuan Liquid (SMZCL), a traditional Chinese herbal formulation, has demonstrated clinical efficacy against asthma, but its und...
BACKGROUND: Airway remodeling is a pivotal pathological driver of asthma progression. Shemazhichuan Liquid (SMZCL), a traditional Chinese herbal formulation, has demonstrated clinical efficacy against asthma, but its underlying molecular mechanisms, particularly regarding airway remodeling, remain to be fully elucidated. PURPOSE: This study aimed to evaluate the therapeutic effects of SMZCL on airway remodeling in asthma and to elucidate the potential molecular mechanisms involved. METHODS: A house dust mite (HDM)-induced asthma mouse model and an epithelial-mesenchymal transition (EMT) cell model were used to evaluate the effects of SMZCL. Histological, biochemical and molecular analyses were performed to assess airway inflammation and remodeling. The chemical constituents of SMZCL were characterized by UHPLC-MS/MS, while network pharmacology and bioinformatics were used to predict key targets and pathways, which were further validated in vivo and in vitro. The functional role of EIF4E was further investigated using AAV-mediated shRNA knockdown in mouse lungs. RESULTS: SMZCL alleviated key asthmatic hallmarks, including inflammatory cell infiltration, mucus secretion, and collagen deposition. It also reduced serum IgE levels, pulmonary cytokine/chemokine profiles, and leukocyte counts in bronchoalveolar lavage fluid (BALF), alongside decreasing airway resistance (RI) and improving lung compliance (Cdyn). Furthermore, SMZCL effectively suppressed the EMT process. A total of 162 chemical constituents were identified, and the key targets were predominantly enriched in mitochondrial, oxidative stress and the HIF-1α signaling pathway, with EIF4E emerging as a top candidate. Molecular docking and surface plasmon resonance (SPR) confirmed a strong binding affinity between EIF4E and two SMZCL-derived compounds, irisflorentin and irigenin. Functional studies further demonstrated that SMZCL mitigated mitochondrial structural damage, enhanced ATP content, mtDNA copy number, and mitochondrial membrane potential, thereby ameliorating mitochondrial dysfunction. In addition, SMZCL reduced oxidative stress by reducing EIF4E/HIF-1α/ROS signaling cascade (evidenced by decreased p-EIF4E, HIF-1α, ROS, p-p65, p-IκBα, IL-6, and TNF-α), leading to reduced levels of 8-OHdG and MDA, while increasing SOD and GPx activity. Notably, AAV-mediated EIF4E silencing mimicked the protective effects of SMZCL by inhibiting the EIF4E/HIF-1α/ROS signaling axis, thereby restoring mitochondrial dysfunction, suppressing oxidative stress and EMT progression to attenuate airway remodeling. CONCLUSION: SMZCL attenuates airway remodeling in asthma by suppressing EMT, a process mediated through the inhibition of the EIF4E/HIF-1α/ROS signaling axis, thereby improving mitochondrial dysfunction and reducing oxidative stress. These findings position SMZCL as a promising therapeutic candidate for asthma airway remodeling.
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