Phytomedicine [JOURNAL]
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200 papers
Delphinidin targets voltage-dependent anion channel 1 to inhibit ferroptosis and protect against retinal photochemical damage.
Wang H, Li K, Pu H … +6 more , Xiong Y, Luo D, Song J, Jiang H, Yu X, Deng T
Phytomedicine · 2026 Jun · PMID 42335641 · Publisher ↗
BACKGROUND: The molecular basis of retinal photochemical damage remains incompletely understood, limiting the development of targeted therapeutic strategies. Delphinidin, an anthocyanidin with reported protective effects...
BACKGROUND: The molecular basis of retinal photochemical damage remains incompletely understood, limiting the development of targeted therapeutic strategies. Delphinidin, an anthocyanidin with reported protective effects, represents a promising candidate, but its direct molecular target and mechanism of action are unclear. METHODS: The molecular target of delphinidin was identified using Activity-Based Protein Profiling (ABPP), DARTS-MS, SPR, and CETSA. Its functional effects were investigated in 661 W photoreceptor cells and in a light-induced retinal damage model in Sprague-Dawley rats. Protein carbonylation was assessed via an alkynylaniline probe, and Voltage-Dependent Anion Channel 1 (VDAC1) oligomerization was examined by chemical crosslinking. Mitochondrial function, cGAS-STING pathway activation, and ferroptosis markers were evaluated to delineate the underlying mechanism. RESULTS: VDAC1 was identified as a direct target of delphinidin. Light exposure induced VDAC1 carbonylation and oligomerization, leading to mitochondrial dysfunction characterized by cytochrome c release and mitochondrial DNA (mtDNA) leakage into the cytosol. Cytosolic mtDNA activated cGAS-STING pathway, which in turn promoted loss of the ferroptosis suppressor GPX4 and triggered ferroptosis. Delphinidin interrupted this cascade by binding to VDAC1 and inhibiting its carbonylation and oligomerization, thus limiting mtDNA leakage, attenuating cGAS-STING activation, preserving GPX4 abundance, and inhibiting ferroptosis. In vivo, delphinidin intervention conferred significant protective effects, as evidenced by preservation of retinal histoarchitecture and reduced oxidative damage and ferroptosis, CONCLUSION: This study identifies a novel mechanistic axis in RPD linking VDAC1 dysregulation to mtDNA-driven innate immune activation and ferroptosis. It further establishes delphinidin as a direct VDAC1 targeting compound and highlights its therapeutic potential for the prevention of RPD.
Echinacoside restores levofloxacin activity against multidrug-resistant Pseudomonas aeruginosa: evidence for iron-responsive siderophore-like properties and membrane disruption.
Tian L, Zhang Y, Zhang B … +11 more , Hu J, Zhang B, Ke C, Xing Y, Zhang Q, Xiong H, Zhou J, Xia J, Li G, Zhao Q, Liang C
Phytomedicine · 2026 Jun · PMID 42335640 · Publisher ↗
BACKGROUND: Drug-resistant Gram-negative infections, particularly those caused by Pseudomonas aeruginosa (P. aeruginosa), remain difficult to treat. Natural products are increasingly explored as antibiotic adjuvants, but...
BACKGROUND: Drug-resistant Gram-negative infections, particularly those caused by Pseudomonas aeruginosa (P. aeruginosa), remain difficult to treat. Natural products are increasingly explored as antibiotic adjuvants, but their mechanisms remain unclear. PURPOSE: To determine whether echinacoside (ECH) enhances levofloxacin activity against drug-resistant P. aeruginosa and whether iron-responsive siderophore-like properties and membrane-associated effects may contribute to this activity. STUDY DESIGN: An integrated study combining in vitro microbiological, cellular, computational, and murine in vivo analyses. METHODS: MICs were determined in standard and iron-depleted cation-adjusted Mueller-Hinton broth. Ferric iron chelation was assessed on chrome azurol S agar. A pyoverdine (PVD)-based competition assay and docking/MD simulations were used to assess iron-associated siderophore-like behavior and structural compatibility of ECH-Fe(III) with a representative catechol-siderophore receptor pocket. Synergy, membrane effects, and in vivo efficacy were examined. RESULTS: ECH showed weak antibacterial activity in standard medium, but activity increased under iron restriction and ECH chelated ferric iron. ECH-Fe(III) caused an iron-responsive reduction in PVD-associated fluorescence signal, consistent with possible interference with a siderophore-associated process under iron-limited conditions. Docking/MD analyses supported structural compatibility of ECH-Fe(III) with a catechol-siderophore receptor pocket. In Escherichia coli and P. aeruginosa, ECH disrupted membrane function and inhibited biofilm formation. In resistant P. aeruginosa, ECH synergized with levofloxacin, reduced levofloxacin MICs, and produced rapid multi-log killing. In vivo, the combination improved survival, reduced organ bacterial burdens, and alleviated tissue injury. CONCLUSION: ECH acted as an iron-responsive, membrane-active antibiotic adjuvant that restored levofloxacin efficacy against drug-resistant P. aeruginosa. The data suggest that iron-responsive siderophore-like properties and membrane-associated effects may contribute to levofloxacin potentiation, while TonB-dependent transport, receptor specificity, and direct uptake remain to be validated.
Ciwujianoside B alleviates cholestatic liver injury by regulating TMAO synthesis via remodeling of the gut microbiota.
Yu D, Jia B, Zu F … +2 more , Zhang W, Guo D
Phytomedicine · 2026 Jun · PMID 42335639 · Publisher ↗
BACKGROUND: Cholestatic liver injury (CLI) is mainly driven by intrahepatic cholestasis, a pathological condition characterized by systemic and intrahepatic accumulation of bile acids. Ciwujianoside B (CWB), the active c...
BACKGROUND: Cholestatic liver injury (CLI) is mainly driven by intrahepatic cholestasis, a pathological condition characterized by systemic and intrahepatic accumulation of bile acids. Ciwujianoside B (CWB), the active constituent of Eleutherococcus senticosus, has demonstrated protective effects in various hepatic pathologies, but its functional role in CLI has not yet been investigated. PURPOSE: This study aims to evaluate the therapeutic potential of CWB against CLI and investigate its mechanism. METHODS: CLI was induced via bile duct ligation, and the protective effects of CWB were assessed through H&E, Sirius red, and immunohistochemical staining. Inflammatory cytokines in serum were measured by ELISA. Integrated analysis of 16S rDNA sequencing, serum metabolomics, and fecal microbiota transplantation was performed to investigate the interactions between gut microbiota and host metabolism. Trimethylamine oxide (TMAO) was supplemented to evaluate its impact on the hepatoprotective effects of CWB. In AML-12 cells, flavin-containing monooxygenase 3 (FMO3) was knockdown or overexpressed to assess TMAO levels, apoptosis, reactive oxygen species (ROS) content, and endoplasmic reticulum (ER) stress. The interaction between CWB and FMO3 was evaluated with molecular docking and molecular dynamics simulations. RESULTS: CWB alleviated hepatocellular damage and apoptosis, which was accompanied by reduced serum levels of ALT, AST, ALP, and inflammatory cytokines. Mechanistic analyses revealed that CWB remodeled the gut microbiota, suppressed Cut C and Cut D levels in feces, thereby reducing systemic TMAO accumulation. Exogenous TMAO supplementation reversed the protective effect of CWB. Antibiotic treatment partially abrogated the hepatic protective effects of CWB. CWB significantly suppressed FMO3 expression. Knockdown of FMO3 in AML-12 cells led to a reduction in intracellular TMAO levels, apoptosis rate, ROS content and ER stress activation. Molecular docking revealed a stable binding interaction between CWB and FMO3. CONCLUSIONS: Our results suggest that CWB alleviates CLI by suppressing TMAO biosynthesis, primarily through reducing trimethylamine-producing bacteria and directly inhibiting hepatic FMO3 expression.
Structural insights into TRPA1 and TRPV1 modulation by flavonoid glycosides from licorice for cough relief.
Yi Y, Duan G, Dai Z … +7 more , Zhou X, Huang J, Jin Z, Yang A, Li Y, Huang Z, Ye M
Phytomedicine · 2026 Jun · PMID 42335638 · Publisher ↗
BACKGROUND: Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) are two nociceptive TRP channel subtypes that play central roles in cough hypersensitivity. PURPOSE: This study evaluated the antitussive...
BACKGROUND: Transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) are two nociceptive TRP channel subtypes that play central roles in cough hypersensitivity. PURPOSE: This study evaluated the antitussive efficacy of liquiritin apioside (LIQA) and liquiritin (LIQ), two major flavonoid glycosides from licorice, in acute chemically induced cough models, and investigated their modulations of TRPA1 and TRPV1. METHODS: In guinea pig models, cough was induced by capsaicin (a TRPV1 agonist) and cinnamaldehyde (a TRPA1 agonist), respectively. The inhibitory effects of LIQA and LIQ against TRPA1 and TRPV1 were assessed using electrophysiological profiling and fluorescence-based calcium assays. To elucidate the underlying mechanisms, high-resolution cryo-electron microscopy (cryo-EM) structural analysis, and molecular simulations were conducted. RESULTS: LIQA and LIQ significantly reduced cough frequency in the guinea pig models. Electrophysiological profiling revealed that LIQA suppressed human TRPA1 (hTRPA1) channel activity, while LIQ blocked human TRPV1 (hTRPV1) activation. High-resolution cryo-EM structures of hTRPA1/LIQA (2.59 Å) and hTRPV1/LIQ (3.05 Å) complexes were obtained. Structural analysis indicates that LIQA stabilizes hTRPA1 in a closed conformation with T624 at the coupling region site, whereas LIQ interacts with S512 through hydrogen bonding in the deep S4-S5 site of hTRPV1, thereby inhibiting pore opening. CONCLUSION: This study establishes LIQA and LIQ as lead compounds with acute antitussive activities mediated by TRPA1/TRPV1 modulation.
Medium-chain inulin reshapes the gut microbiome-metabolome axis to counteract high-fat diet-induced obesity.
Wang Y, Kim E, Cui J … +2 more , Lee Y, Zhang G
Phytomedicine · 2026 Jun · PMID 42322766 · Publisher ↗
BACKGROUND: Inulin, a natural dietary fiber, exerts diverse health benefits that are closely linked to its molecular structure. However, the biological activity of medium-chain inulin and its role in high-fat diet (HFD)-...
BACKGROUND: Inulin, a natural dietary fiber, exerts diverse health benefits that are closely linked to its molecular structure. However, the biological activity of medium-chain inulin and its role in high-fat diet (HFD)-induced obesity remain poorly characterized. OBJECTIVE: This study aimed to determine whether medium-chain inulin could alleviate high-fat diet (HFD)-induced obesity by modulating the gut microbiota and metabolome, thereby restoring metabolic homeostasis. METHODS: Forty male C57BL/6 mice were fed either a standard chow diet or an HFD with 1%, 3%, or 5% medium-chain inulin (average degree of polymerization = 12) for 12 weeks. Body weight (BW), physiological indices, gut microbiota, and metabolome were analyzed to elucidate the underlying mechanisms. Short-chain fatty acids (SCFAs) were quantified by gas chromatography. Cecal microbiota and metabolome were analyzed using 16S rRNA sequencing and LC-MS/MS, respectively. Correlation and pathway analyses were conducted to identify key microbe-metabolite interactions. RESULTS: Medium-chain inulin supplementation significantly reduced BW gain (by 16% and 20% at 3% and 5% doses, respectively), increased acetic and butyric acid levels, and improved serum and hepatic lipid profiles. It reshaped the gut microbiota by enriching Faecalibaculum, Bifidobacterium, Parasutterella, Clostridium_sensu_stricto_1, Bacteroides, Lactobacillus, and Akkermansia. Metabolomic analysis revealed elevated levels of eight key metabolites related to tryptophan metabolism and bile acid metabolism, correlating with improved metabolic indicators. CONCLUSION: Medium-chain inulin alleviated HFD-induced obesity by remodeling the gut microbiome-metabolome axis and promoting SCFA production. These findings highlight its potential as a functional prebiotic candidate for obesity-related metabolic disorders.
Study of α-Amyrin targeting Sirt1/PGC-1α/PPARα axis to regulate fatty acid metabolism against liver fibrosis.
Wang X, Su G, Ge F … +9 more , Miao W, Li L, Li Z, Yu J, Jiang H, Ma Y, Yu Z, Ren Z, Liang H
Phytomedicine · 2026 Jun · PMID 42322765 · Publisher ↗
BACKGROUND: Hepatic fibrosis represents a major global health burden with no approved first-line therapeutic agents. The urgent need for innovative targeted small molecule interventions has prompted investigation of natu...
BACKGROUND: Hepatic fibrosis represents a major global health burden with no approved first-line therapeutic agents. The urgent need for innovative targeted small molecule interventions has prompted investigation of natural compounds with anti-fibrotic potential. While α-amyrin demonstrates established anti-inflammatory properties, its therapeutic efficacy against hepatic fibrosis remains unexplored. PURPOSE: The present study was designed to assess the anti-fibrotic efficacy of α-amyrin and determine its molecular mechanisms of action. STUDY DESIGN: Firstly, the efficacy of α-Amyrin was evaluated through the liver fibrosis model. Further, the mechanism of α-Amyrin was analyzed using multi-omics and molecular biology experiments, and was verified using the target knockdown model. Finally, the effective components of α-Amyrin were analyzed through bioinformatics analysis and experimental verification. METHODS: In this study, we use an in vitro model of fibrosis in human hepatic stellate LX-2 cells induced with TGF-β1 and an in vivo mouse model with CCl to evaluate the anti-fibrosis potential of α-Amyrin using multiple approaches. Employing multi-omics and molecular biology techniques to investigate the mechanism of α-Amyrin counteracting hepatic fibrosis. The interaction targets of α-Amyrin were examined through molecular docking, molecular dynamics simulations, and surface plasmon resonance. The anti-hepatic fibrosis mechanism of α-Amyrin was further validated using both in vitro and in vivo PPARα knockout or inhibition models. RESULTS: In vivo, α-Amyrin significantly inhibited the formation of hepatic pseudolobules and suppressed hepatic inflammation compared with the model control group. In vitro, α-Amyrin significantly down-regulated the expression levels of well-established markers of liver fibrosis. The results of transcriptomics and metabolomics provided clues to the mechanisms of the PPARα pathway and fatty acid metabolism. Further experimental validation of these mechanisms was conducted. In vitro and in vivo, α-Amyrin significantly promoted fatty acid oxidation levels which is consistent with up-regulation of PPARα pathway involved in this process, including Sirt1, PPARα, PGC-1α, CPT1A, ACOX1, and its downstream targets. Moreover, α-Amyrin markedly enhanced PPARα nuclear translocation and facilitated the Sirt1-PGC-1α interaction. Molecular docking, dynamics simulations, and surface plasmon resonance confirmed direct binding of α-Amyrin to PPARα. Critically, the anti-hepatic fibrosis effect of α-Amyrin was significantly compromised in both the in vivo PPARα inhibitor model and the in vitro PPARα knockout model. CONCLUSIONS: The possible mechanism of α-Amyrin's anti-fibrosis effect is to target the PPARα axis to promote the reprogramming of fatty acid oxidation metabolism, which in turn exerts an anti-inflammatory effect and reverses the inflammation-fibrosis pathological process. The above results are expected to provide an innovative strategy for the development of small molecule drugs targeting liver fibrosis.
Pterostilbene mitigates intervertebral disc degeneration via dual regulation of mitophagy and NLRP3 ubiquitination to inhibit nucleus pulposus cell pyroptosis.
Zhang Y, Liu S, Dong S … +8 more , Song G, Wang K, Zhou Z, Yang G, Yang X, Peng S, Zhang Y, Wu D
Phytomedicine · 2026 Jun · PMID 42322764 · Publisher ↗
BACKGROUND: Intervertebral disc degeneration (IVDD) is a major contributor to low back pain and is characterized by mitochondrial dysfunction, inflammation, and regulated cell death in nucleus pulposus (NP) cells. NLRP3...
BACKGROUND: Intervertebral disc degeneration (IVDD) is a major contributor to low back pain and is characterized by mitochondrial dysfunction, inflammation, and regulated cell death in nucleus pulposus (NP) cells. NLRP3 inflammasome-mediated pyroptosis plays a pivotal role in disc degeneration, whereas mitophagy limits mitochondrial damage and inflammasome activation. Emerging evidence indicates that pterostilbene (PTE) exhibits diverse pharmacological activities; however, its role in attenuating IVDD remains insufficiently understood. OBJECTIVE: To investigate whether PTE attenuates IVDD by regulating mitophagy and NLRP3 inflammasome-mediated pyroptosis, and to elucidate the underlying molecular mechanisms. STUDY DESIGN: This study combined network pharmacology analysis, in vitro cellular experiments, and an in vivo rat IVDD model to evaluate the therapeutic effects and mechanisms of PTE. METHODS: Network pharmacology was used to predict the cytoprotective potential of PTE. In vitro, LPS-stimulated NP cells were employed to evaluate inflammation, extracellular matrix degradation, pyroptosis, mitochondrial function, and mitophagic flux. Pharmacological inhibitors were used to interrogate mitophagy-dependent mechanisms, while Western blotting, co-immunoprecipitation, and related assays were performed to assess signaling pathways, protein stability, and ubiquitination. In vivo, a rat IVDD model was established to evaluate the therapeutic effects of PTE through radiological and histopathological analyses. RESULTS: PTE attenuated LPS-induced inflammatory responses and extracellular matrix degradation in NP cells. It suppressed NLRP3 inflammasome-mediated pyroptosis and restored mitochondrial function by enhancing mitophagic flux, whereas inhibition of mitophagy partially reversed these protective effects. Mechanistically, PTE activated the AMPK/mTOR/ULK1 signaling pathway to promote mitophagy. In parallel, PTE facilitated ubiquitination and proteasomal degradation of NLRP3, predominantly through K48-linked polyubiquitination, while K63-linked modification may contribute to regulatory signaling. Notably, this ubiquitination-mediated degradation occurred independently of mitophagy. In vivo, PTE significantly alleviated disc degeneration, reduced NLRP3, caspase-1, and p-mTOR expression, and increased collagen II, SOX9, PINK1, LC3, and p-AMPK levels. CONCLUSION: PTE attenuates IVDD progression by coordinately enhancing mitophagy and promoting K48-linked ubiquitin-proteasome-dependent degradation of NLRP3. These two mechanisms operate independently yet synergistically to suppress inflammasome activation, providing mechanistic insight into PTE as a potential disease-modifying therapeutic strategy for IVDD.
Zanthoxylum nitidum-derived active alkaloid nitidine chloride mitigates ulcerative colitis by remodeling gut microbiota and activating SIRT1 to restore intestinal barrier integrity.
Lu Q, Chen R, Wei S … +4 more , Zheng D, Chen H, Zhao L, Li C
Phytomedicine · 2026 Jun · PMID 42322763 · Publisher ↗
BACKGROUND: Ulcerative colitis (UC) is a recurrent inflammatory bowel disorder with rising prevalence and limited efficacy of current treatments. Nitidine chloride (NC), a characteristic bioactive constituent of Zanthoxy...
BACKGROUND: Ulcerative colitis (UC) is a recurrent inflammatory bowel disorder with rising prevalence and limited efficacy of current treatments. Nitidine chloride (NC), a characteristic bioactive constituent of Zanthoxylum nitidum (Liang-Mian-Zhen), possesses diverse pharmacological properties, including anti-inflammatory, antitumor, and antioxidant activities. Nevertheless, its role in UC and the associated regulatory mechanisms remain incompletely defined. PURPOSE: This study investigated whether NC protects against experimental colitis and clarified its effects on epithelial barrier integrity, gut microbial composition, and SIRT1-associated regulation of endoplasmic reticulum (ER) stress and TLR4/NF-κB signaling. METHODS: Experimental colitis was established using 3% dextran sulfate sodium (DSS)-treated mice, while LPS-stimulated Caco-2 cells were used to evaluate epithelial barrier dysfunction in vitro. Disease severity, barrier integrity, and gut microbial alterations were assessed by histological, permeability-related, and 16S rRNA sequencing analyses. Transepithelial electrical resistance (TEER) and FITC-dextran assays were applied to evaluate epithelial permeability. ER stress, TLR4/NF-κB signaling, inflammatory mediators, and SIRT1-related mechanisms were examined by Western blot, qRT-PCR, ELISA, molecular docking, cellular thermal shift assay (CETSA), pharmacological inhibition with EX-527, and SIRT1 overexpression. RESULTS: NC markedly alleviated DSS-induced colitis, as evidenced by reduced clinical symptoms, attenuated histological injury, and improved intestinal barrier function. NC restored ZO-1, occludin, and mucin 2 (MUC2) expression, improved Alcian blue-positive goblet cell area, and reduced serum DAO and d-lactate levels. Microbiota analysis showed that NC partly corrected DSS-induced gut microbial dysbiosis and reshaped predicted microbial functions. In LPS-stimulated Caco-2 cells, NC improved barrier integrity by increasing TEER, reducing FITC-dextran permeability, and restoring tight junction protein expression. Mechanistically, NC increased SIRT1 expression and suppressed the PERK-eIF2α-ATF4-CHOP and TLR4/NF-κB pathways both in vivo and in vitro. CETSA further supported target engagement between NC and SIRT1 in Caco-2 cells. Moreover, EX-527 largely abolished the protective effects of NC, whereas SIRT1 overexpression attenuated LPS-induced ER stress and inflammatory signaling. CONCLUSION: NC exerted significant protective effects against experimental UC by alleviating inflammation, preserving epithelial and mucus barrier integrity, and partially restoring gut microbial homeostasis. These effects were associated, at least in part, with SIRT1-mediated suppression of ER stress and TLR4/NF-κB signaling. NC may represent a promising natural agent for UC therapy.
Lichang decoction suppresses AOM+DSS-induced colitis-associated cancer via regulating intestinal flora and suppressing the Wnt/β-catenin signaling pathway.
Xie Y, Lin J, Huang Z … +7 more , Jiang D, Peng L, Luo Y, Liang J, Han Y, Guo S, Jiang X
Phytomedicine · 2026 Jun · PMID 42322762 · Publisher ↗
BACKGROUND: Lichang Decoction (LCD), a traditional Chinese medicine formula clinically used for intestinal disorders, has shown anti-inflammatory potential; however, its therapeutic efficacy and underlying mechanism in c...
BACKGROUND: Lichang Decoction (LCD), a traditional Chinese medicine formula clinically used for intestinal disorders, has shown anti-inflammatory potential; however, its therapeutic efficacy and underlying mechanism in colitis-associated colorectal cancer (CAC) remain unclear. PURPOSE: The objective of this study is to investigate the effects and mechanisms of LCD in an AOM+DSS-induced CAC mouse model. METHODS: The primary constituents of LCD were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). An azoxymethane/dextran sulfate sodium (AOM+DSS)-induced CAC mouse model was established and treated with low- or high-dose LCD, or 5-fluorouracil (5-Fu). Clinical symptoms, tumor burden, histopathological changes and inflammatory responses were evaluated. Intestinal barrier integrity was assessed by tight junction and mucus-related markers. Transcriptomic analysis, quantitative PCR and Western blotting were performed to investigate the Wnt/β-catenin signaling pathway. Gut microbiota alterations were analyzed by 16S rRNA sequencing, and fecal microbiota transplantation (FMT) was conducted to determine the causal role of microbiota in LCD-mediated protection. RESULTS: LCD treatment significantly alleviated weight loss, diarrhea and hematochezia, reduced disease activity index scores, and markedly suppressed tumor number and size in CAC mice. LCD attenuated colonic inflammation by decreasing serum and tissue levels of IL-1β, TNF-α, IL-6 and IFN-γ, while reducing CD11b⁺ and MPO⁺ inflammatory cell infiltration. Moreover, LCD restored intestinal barrier function and increased goblet cell abundance. Mechanistically, transcriptomic, molecular analyses and molecular docking revealed that LCD significantly inhibited aberrant activation of the Wnt/β-catenin pathway, evidenced by reduced expression of Wnt4, β-catenin, c-Myc and cyclin D1. However, LCD treatment in HCT116 cells did not affect the Wnt/β-catenin pathway. Additionally, LCD reshaped gut microbiota composition by suppressing tumor-associated bacterial taxa (Bacillota and Bacteroidota) and enriching beneficial Verrucomicrobiota. Correlation and functional prediction analyses linked microbial modulation to Wnt/β-catenin signaling and tumor progression. Importantly, FMT derived from LCD exerted an inhibitory effect on tumor progression in pseudo-germ-free CAC mice, but direct administration of LCD in pseudo-germ-free CAC mouse model did not demonstrate a significant tumor-suppressive effect. CONCLUSION: LCD effectively suppresses CAC by remodeling gut microbiota to inhibit Wnt/β-catenin signaling, thereby alleviating inflammation, restoring intestinal barrier function and restraining tumor progression. These findings indicate that LCD represents a viable therapeutic intervention for CAC treatment.
Oxymatrine alleviates cerebral ischemia-reperfusion injury by inhibiting microglia ferroptosis via NRF2 pathway activation.
Wu N, Wang Y, Guo M … +6 more , Ran R, Wang D, Song J, Hui L, Yang J, Yang Y
Phytomedicine · 2026 Jun · PMID 42322761 · Publisher ↗
BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) involves secondary damage following blood flow restoration. Ferroptosis, an iron-dependent cell death process, is implicated in CIRI, with mitochondrial dynamics im...
BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) involves secondary damage following blood flow restoration. Ferroptosis, an iron-dependent cell death process, is implicated in CIRI, with mitochondrial dynamics imbalance playing a critical role. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the root of Sophora flavescens, exhibits neuroprotective properties, yet its role in modulating microglia ferroptosis and mitochondrial homeostasis during CIRI remains unclear. PURPOSE: This study aimed to investigate whether OMT attenuates microglia ferroptosis in CIRI by activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway and restoring mitochondrial dynamic balance. METHODS: Using a rat middle cerebral artery occlusion/reperfusion model and BV-2 microglia under oxygen-glucose deprivation/reoxygenation, we evaluated the effects of OMT alone or with NRF2 inhibitor ML385 or ferroptosis inducer Erastin. Assessments included neurological scores, infarct volume, Reactive Oxygen Species, ferrous iron, malondialdehyde, glutathione, mitochondrial membrane potential, and related protein expression, including NRF2, kelch-like ECH-associated protein 1 (KEAP1), heme oxygenase-1, solute carrier family 7 member 11, ferritin heavy chain, glutathione peroxidase 4, dynamin-related protein 1, optic atrophy 1. Molecular docking, surface plasmon resonance, and co-immunoprecipitation were used to examine OMT-KEAP1 binding. Finally, in vitro rescue experiments using KEAP1 overexpression and CDDO-ME (a specific KEAP1 inhibitor) confirmed the KEAP1/NRF2 dependency by re-assessing cell viability and ferroptosis markers. RESULTS: OMT improved neurological outcomes and suppressed ferroptosis in vivo and in vitro. Mechanistically, OMT disrupted KEAP1-NRF2 binding, promoting NRF2 nuclear translocation and upregulating solute carrier family 7 member 11, heme oxygenase-1, ferritin heavy chain, and glutathione peroxidase 4. This restored mitochondrial homeostasis by balancing optic atrophy 1 and dynamin-related protein 1, thereby reducing lipid peroxidation. Crucially, these effects were abolished by ML385 or Erastin, while KEAP1 overexpression and CDDO-ME respectively mimicked KEAP1-mediated suppression and NRF2-driven protection. These findings confirm OMT acts via a KEAP1/NRF2-dependent anti-ferroptotic axis. CONCLUSIONS: OMT protects against CIRI by inhibiting microglia ferroptosis through NRF2 pathway activation and improvement of mitochondrial homeostasis, supporting its potential as a therapeutic agent for ischemic stroke.
ROS-NRF2 axis coordinates concentration-graded differentiation-to-PANoptosis switching in a phthalide combination therapy for acute myeloid leukemia.
Luo M, Xia M, Chen Z … +4 more , Wang Q, Yin Y, Li L, Qi H
Phytomedicine · 2026 Jun · PMID 42322760 · Publisher ↗
BACKGROUND: In the context of multimodal therapeutic strategies for acute myeloid leukemia (AML), the coordinated regulation of cell death and differentiation pathways has emerged as a groundbreaking research direction....
BACKGROUND: In the context of multimodal therapeutic strategies for acute myeloid leukemia (AML), the coordinated regulation of cell death and differentiation pathways has emerged as a groundbreaking research direction. PURPOSE: the study aims to investigates the synergistic anti-AML mechanisms of two phthalide derivatives from Chuanxiong Rhizoma, Z-Ligustilide (Z-LIG, a potent pro-apoptotic agent) and Senkyunolide A (Sen-A, a differentiation inducer). METHODS: The anticancer activity of Z-LIG and Sen-A, and their synergistic effects, were evaluated using the SRB assay. The cells underwent differentiation and PANoptosis (the forms of cell death with apoptosis, pyroptosis and necroptosis at same time), as evidenced by alterations in cell morphology observed through flow cytometry and transmission electron microscopy (TEM). The upregulation of NRF2 in both differentiation and PANoptosis was confirmed through the use of inhibitors (ML385, Dicoumarol), and the examination of ROS levels in differentiation and PANoptosis through flow cytometry. Finally, the findings were validated in an AML-NOD/SCID mouse model. RESULTS: In vitro experiments revealed that Z-LIG/Sen-A combination triggers concentration -dependent dual effects in AML cells: low- concentration treatment promotes differentiation via HO-mediated reprogramming of iron homeostasis, whereas high- concentration administration induces PANoptosis through ASC-RIPK3-caspase-8 inflammasome assembly driven by HO accumulation. Mechanistically, a bidirectional regulatory network between ROS and NRF2 orchestrates both iron metabolism and PANoptosis pathways. In AML-NOD/SCID murine models, the combination therapy significantly attenuated leukemia progression and activated the bone marrow NRF2/ROS axis without inducing nephrotoxicity. CONCLUSION: The study pioneers the elucidation of phthalide-induced "differentiation-to-PANoptosis" fate switching governed by HO dosage gradients and NRF2/ROS crosstalk, providing a mechanistic framework for developing precision TCM-based combinatorial therapies against hematological malignancies.
EGCG inactivates tumor necrosis factor-alpha (TNFα) by inducing its higher-order assembly.
Xu H, Du C, Chen Y … +12 more , Liu T, An S, Jiang Z, Chang H, Su C, Li Q, Liang H, Tao H, Ru H, Hua T, Song G, Sheng J
Phytomedicine · 2026 Jun · PMID 42322759 · Publisher ↗
BACKGROUND: Tumor necrosis factor-alpha (TNFα) is an important therapeutic target for treating a range of inflammatory and autoimmune disorders. The TNFα trimer functions by interacting with its receptors (TNFRs) on the...
BACKGROUND: Tumor necrosis factor-alpha (TNFα) is an important therapeutic target for treating a range of inflammatory and autoimmune disorders. The TNFα trimer functions by interacting with its receptors (TNFRs) on the immune cell surface and triggers downstream intracellular signaling. (-)-Epigallocatechin-3-gallate (EGCG) is the primary bioactive polyphenol compound in green tea. Our previous study found that EGCG can inhibit TNFα activity; however, the underlying molecular mechanism remains unclear. PURPOSE: In this study, we investigated the interaction between EGCG and TNFα to elucidate the mechanism by which EGCG inactivates TNFα. METHODS: EGCG-treated TNFα was analyzed using size exclusion chromatography (SEC), multiangle light scattering (MALS), and cryo-electron microscopy (cryo-EM). Mass spectrometry (MS), chemical modifications, and cell-based assays were further conducted to assess the function of the endogenous cysteines. RESULTS: EGCG induces assembly of TNFα trimers into higher-order aggregation states, characterized as a non-strictly defined oligomerization. This process involves reorganization of the endogenous disulfide bond (C69-C101) through reduction and subsequent oxidation reactions. The resulting oligomers are incapable of triggering TNFα-TNFR signaling, and capping the free cysteines in TNFα abrogates the inhibitory effect of EGCG. CONCLUSION: These findings reveal the molecular basis for the beneficial effect of EGCG in TNFα-associated inflammatory and autoimmune diseases, giving a new support to the consumption of regular green tea as a dietary therapy. This approach may be particularly relevant in the post-COVID-19 context for managing long COVID symptoms linked to elevated TNFα levels.
Discovery of natural inhibitors against gut bacterial β-glucuronidase from Arnebia euchroma for mitigating irinotecan-induced colitis.
Liu YO, Shen MY, Yang HL … +5 more , Yin WW, Jia-Liu, Zhao WY, Lv X, Ma XC
Phytomedicine · 2026 Jun · PMID 42320218 · Publisher ↗
BACKGROUND: Gut bacterial β-glucuronidase (GUS) is essential for enterohepatic circulation, by reactivating drug metabolites within the intestine and exerting toxicological effects. GUS inhibitors have shown great clinic...
BACKGROUND: Gut bacterial β-glucuronidase (GUS) is essential for enterohepatic circulation, by reactivating drug metabolites within the intestine and exerting toxicological effects. GUS inhibitors have shown great clinical potential for the alleviation of drug-induced intestinal toxicity. PURPOSE: To discover and characterize natural GUS inhibitors from traditional Chinese medicine (TCM) for the prevention and treatment of irinotecan-induced intestinal toxicity. METHODS: A fluorescence-based screening platform was established to evaluate GUS inhibitors from TCM. A mouse model of irinotecan-induced intestinal toxicity was developed to assess the therapeutic efficacy of Arnebia euchroma (Royle ex Benth.) I.M.Johnst. (Zicao). Bioactive compounds were isolated and purified from Zicao using a preparative high-pressure liquid chromatography (HPLC) instrument. In addition, enzyme kinetics, molecular docking, and molecular dynamics simulations were employed to elucidate specific inhibitory mechanisms. RESULTS: Zicao exhibited potent GUS inhibitory activity, reversed irinotecan-induced GUS elevation, and relieved irinotecan-induced intestinal toxicity in mice. Phytochemical investigation identified 28 compounds from Zicao, including seven potent GUS inhibitors: shikonofurans (A, E, F, and J) and arnebinols (A, B, and C). Shikonofuran A acted as a non-competitive inhibitor by bonding to the amino acid residues Tyr397, Gln396, and Asn444 of GUS and exhibited direct anti-inflammatory effects by suppressing LPS-induced cytokine secretion in mouse macrophages. CONCLUSIONS: Zicao alleviated irinotecan-induced intestinal toxicity via potent GUS inhibition. Shikonofurans (A, E, F, J) and arnebinols (A, B, C) were identified and characterized as responsible for the inhibitory effect of Zicao on GUS. Zicao and its derivatives may serve as adjuvant therapeutics for mitigating irinotecan-induced intestinal toxicity in the clinic.
Qi Wei Zhi Gan formulation alleviates progressive fibrosis in metabolic dysfunction-associated steatohepatitis through suppressing Peroxidasin-collagen IV crosslinking.
Song D, Zhang Z, Sheng W … +6 more , Xiang Y, Zhang X, Xiang Y, Ji G, Lu L, Zhang L
Phytomedicine · 2026 Jun · PMID 42320088 · Publisher ↗
BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder involving steatosis, inflammation, and frequent fibrosis. Qi Wei Zhi Gan (QWZG) formulation, a traditional Chinese herba...
BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder involving steatosis, inflammation, and frequent fibrosis. Qi Wei Zhi Gan (QWZG) formulation, a traditional Chinese herbal formulation, has demonstrated therapeutic effects against MASH though its mechanisms remain not fully elucidated. PURPOSE: This study investigates the anti-fibrotic effects of QWZG formulation and explores its mechanism related to extracellular matrix (ECM) remodeling. METHODS: MASH was induced in mice by choline-deficient, l-amino acid-defined (CDAA) diet. QWZG efficacy was assessed via lipid profiles, liver function biomarkers, and histology. Proteomics identified candidate targets, validated by RT-qPCR, western blot, and immunofluorescence in primary hepatocytes. To explore potential mechanistic involvement, an in vivo experiment was performed using adenovirus-mediated Pxdn overexpression (Pxdn_OE) in CDAA-fed mice, with or without QWZG treatment. Human bulk, single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics analyses support the key target and mechanism in MASH fibrosis. RESULTS: QWZG treatment markedly reduced obesity, hepatomegaly, and lipid accumulation, and inflammation in MASH model. Proteomics revealed strong modulation of ECM and fibrosis pathway, with downregulation of Col1a1 and αSMA. Specifically, Pxdn emerged as the most upregulated protein in MASH mice and was suppressed following QWZG, an effect notably predominant in hepatocytes. Immunofluorescence further revealed colocalization of Pxdn and Col4a1 in primary hepatocytes. QWZG potently inhibited Pxdn-driven Col4a1 crosslinking, this suppression subsequently reduced the expression of fibrotic markers such as αSMA and Col1a1, indicating suppressed hepatic stellate cell activation. Adenovirus-mediated Pxdn_OE in CDAA-fed mice enhanced Pxdn-Col4a1 colocalization, indicating increased crosslinking activity, which was reversed by QWZG. SnRNA-seq and spatial transcriptomics further demonstrated a strong association between Pxdn expression and Col4a1, especially for fibrosis severity, supporting clinical relevance. CONCLUSION: QWZG ameliorates liver fibrosis, which may be partly mediated by inhibition of Pxdn-mediated collagen IV crosslinking, reducing ECM deposition and improving basement membrane microenvironment. These results highlight the potential of QWZG as a novel therapeutic strategy for MASH.
Xiaoyao San attenuates postmenopausal atherosclerosis via ERα-mediated suppression of hepatic PCSK9 transcription.
Jing Y, Yao Y, Xiong Q … +3 more , Yuan J, Zhang H, Hu T
Phytomedicine · 2026 Jun · PMID 42320087 · Publisher ↗
BACKGROUND: Postmenopausal women exhibit elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, increasing atherosclerosis risk. Xiaoyao San (XYS), a classic herbal formula renowned for its ability to soo...
BACKGROUND: Postmenopausal women exhibit elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, increasing atherosclerosis risk. Xiaoyao San (XYS), a classic herbal formula renowned for its ability to soothe the liver and relieve depression, is widely used in China to manage perimenopausal syndrome. Previous studies have found that it alleviates hepatic lipid accumulation through the Estrogen receptor α (ERα) signaling pathway, but its role in postmenopausal atherosclerosis via the PCSK9 regulatory mechanism remains unclear. PURPOSE: This study investigated XYS effects on delaying postmenopausal atherosclerosis by modulating hepatic PCSK9 transcription. METHODS AND RESULTS: ApoE⁻/⁻ mice underwent bilateral ovariectomy and were fed a high-fat and high-fructose diet for 14 weeks to establish a postmenopausal atherosclerosis model. Using H&E staining, Oil Red O staining, Western blotting, and immunofluorescence, XYS reduced hepatic/serum PCSK9 and upregulated LDLR, attenuating dyslipidemia and atherosclerosis. Mechanistically, RNA-seq identified estrogen receptor signaling and the LXRα/SREBP-1c axis of fatty acid synthesis as the key molecular pathways. XYS upregulated ERα, suppressing LXRα/SREBP-1c-mediated hepatic steatosis and PCSK9 transcription. Consistent results were observed in insulin-treated cell models. Luciferase reporter assays demonstrated that XYS reduced sterol regulatory element (SRE)-dependent PCSK9 promoter activity. Notably, both in vivo targeted knockdown of hepatic ERα and in vitro treatment with the ERα antagonist ICI 182,780 reversed XYS-induced suppression of LXRα/SREBP-1c-mediated PCSK9 transcription, highlighting the critical role of hepatic ERα activation in XYS's inhibition of postmenopausal atherosclerosis progression. CONCLUSIONS: XYS attenuates postmenopausal atherosclerosis by inhibiting hepatic PCSK9 transcription via ERα-mediated LXRα/SREBP-1c suppression, revealing a novel phytoestrogenic mechanism and potential as a natural PCSK9 inhibitor for cardiovascular protection.
Huaganjian decoction attenuates liver fibrosis via purine metabolic-inflammatory synergistic crosstalk: network pharmacology combined with multi-omics analyses.
Zhang Y, Su W, Chen W … +6 more , Yao S, Chen S, Wang S, Zhao D, Liu H, Liu M
Phytomedicine · 2026 Jun · PMID 42320086 · Publisher ↗
BACKGROUND AND PURPOSE: Liver fibrosis (LF) is a precursor to cirrhosis. Approved therapies remain limited and are restricted to specific etiologies, necessitating effective anti-LF interventions. Huaganjian decoction (H...
BACKGROUND AND PURPOSE: Liver fibrosis (LF) is a precursor to cirrhosis. Approved therapies remain limited and are restricted to specific etiologies, necessitating effective anti-LF interventions. Huaganjian decoction (HGJD) has long been used for chronic liver diseases. However, the mechanism of action and active components remain unclear. This study aimed to characterize anti-LF efficacy of HGJD and clarify its mechanism through a phenotype-component-target-pathway evidence chain. METHODS AND RESULTS: The anti-LF efficacy of HGJD was first evaluated in CCl-induced mouse LF and TGF-β1-stimulated hepatic stellate cell (HSC) activation models. HGJD alleviated hepatic injury and fibrotic remodeling, reduced collagen deposition, extracellular matrix accumulation, inflammatory mediators, and fibrogenic markers. It also suppressed HSC proliferation and migration while promoting apoptosis and cell-cycle arrest. The chemical composition of HGJD was profiled using UPLC-Q-Exactive MS/MS, and network pharmacology identified inflammation as a key hub, linking HGJD active compounds to fibrosis-related targets. Integrated metabolomics and transcriptomics converged on the reversal of a metabolism-inflammation imbalance. HGJD exerts multi-component synergistic effects to modulate pathological networks through a dual mechanism: by reducing adenosine levels, thereby removing a critical upstream metabolic trigger, and by directly inhibiting the signaling pathway. The dual mechanism, supported by loss-of-function, gain-of-function, and adenosine rescue experiments, allowed HGJD to inhibit HSC activation, reduce extracellular matrix accumulation-related protein expression and deposition, and promote fibrosis regression. CONCLUSION: HGJD mitigates LF by reprogramming the metabolism-inflammation-fibrosis axis, centered on blockade of the NF-κB/NLRP3/IL-18 feed-forward circuit, providing a mechanistic rationale for its multi-component anti-LF potential.
Rosmarinic acid inhibits non-small cell lung cancer progression by directly targeting KRAS and modulating the KRAS/AKT/ERK signaling axis.
Zhao W, Zhang Q, He Y … +13 more , Xing X, An Y, Zhang Y, Li W, Yang S, Xiong X, He W, Wong YK, Yang S, Rao S, Feng Y, Luo P, Wang J
Phytomedicine · 2026 Apr · PMID 42320085 · Publisher ↗
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a significant health challenge, and the KRAS mutation plays a critical role in its development, especially KRAS. Rosmarinic acid (RA), a natural polyphenolic compoun...
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a significant health challenge, and the KRAS mutation plays a critical role in its development, especially KRAS. Rosmarinic acid (RA), a natural polyphenolic compound, has demonstrated robust anti-cancer activities. However, the precise molecular mechanisms underlying its anti-tumor effects in NSCLC remain poorly understood. METHODS: We assessed RA's anti-tumor effects in vitro/in vivo NSCLC models. Activity-based protein profiling (ABPP) coupled with bioorthogonal click chemistry identified RA's direct molecular targets. Western blot and other techniques analyzed KRAS/AKT/ERK signaling, plus cell cycle/apoptosis molecule expression. The effect of RA on tumor suppression and the ability of tumor cells to evade macrophages in an NSCLC mouse model with KRAS mutation was evaluated. RESULTS: RA significantly inhibited NSCLC cell proliferation and induced apoptosis by modulating the KRAS/AKT/ERK signaling cascade. ABPP analysis revealed that RA directly binds to KRAS at the mutant cysteine-12 residue. Functional studies confirmed that RA-mediated cell cycle arrest and apoptosis depend on KRAS modulation. In KRAS-mutant mouse models, RA markedly suppressed tumor growth and reduced macrophage evasion by tumor cells. CONCLUSIONS: RA acts as a novel KRAS inhibitor that directly targets the mutant cysteine-12 residue, suppressing NSCLC progression through inhibition of the KRAS/AKT/ERK pathway and enhancement of anti-tumor immune activity. These findings highlight RA's therapeutic potential for KRAS-driven NSCLC and offer new insights for the development of targeted cancer therapies.
Betulinic acid regulates microglial polarization by inhibiting the phosphorylation of CB2 receptors thereby improving ischemic brain injury.
Guo Y, Wang G, Tian Q … +9 more , Li Y, Zhao Q, Kang Y, Liu C, He P, Wang J, Liao J, Deng G, Li M
Phytomedicine · 2026 Jun · PMID 42314352 · Publisher ↗
Ischemic stroke is a leading cause of mortality and permanent disability worldwide, with a lack of effective drug therapy. Microglia, as the intrinsic immune cells of the brain, play a biphasic role in ischemic stroke de...
Ischemic stroke is a leading cause of mortality and permanent disability worldwide, with a lack of effective drug therapy. Microglia, as the intrinsic immune cells of the brain, play a biphasic role in ischemic stroke depending on its polarization toward M1 or M2 phenotype. Betulinic acid (BA) is a natural bioactive compound has antioxidant, anti-inflammatory, anti-tumor, and other biological activities, holds potential to active CB2 receptor on microglia and promote a shift towards the M2 polarization. This study delves into the regulatory impact of self-assembled BA on CB2 receptor-mediated microglial polarization after cerebral ischemia. In vitro studies revealed BA's ability to modulate the polarization of BV2 microglia subjected to lipopolysaccharide (LPS) treatment, an effect impeded by CB2 inhibition. For in vivo studies, transient middle cerebral artery occlusion (MCAO) model mice receiving self-assembled BA NPs exhibited the smallest infarct volume and least neurological deficits. However, these benefits were reversible with the administration of a CB2 inhibitor. Notably, microglia at the ischemic site displayed a shift towards the M2 phenotype upon BA treatment. Our results demonstrates that BA can significantly regulate the M1/M2 polarization of microglia by activating CB2 signal and inhibiting its phosphorylation level in ischemic stroke, thereby reducing the brain inflammatory response and playing a neuroprotective role.
Salvianolic acid B attenuates drug-induced liver injury in an Nrf2-dependent mechanism via covalently modifying Keap1 at Cys395/Cys434.
Zhang Z, Gu X, Zhu G … +7 more , Meng Y, Wei M, Chu X, Luo Y, Huang Z, Ge G, Ji L
Phytomedicine · 2026 Jun · PMID 42314351 · Publisher ↗
BACKGROUND: Drug-induced liver injury (DILI) is a global health issue with limited treatment options. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a critical role in defending against DI...
BACKGROUND: Drug-induced liver injury (DILI) is a global health issue with limited treatment options. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway plays a critical role in defending against DILI, making it a potential therapeutic target. PURPOSE: This study aimed to investigate the hepatoprotective effect of salvianolic acid B (Sal B), a polyphenol derived from Salvia miltiorrhiza Bge., against DILI and to elucidate its underlying molecular mechanisms, particularly focusing on the Nrf2 pathway. METHODS: Compounds screening was carried out to identify Sal B as a potent Nrf2 activator. Cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and microscale thermophoresis (MST) were employed to examine the direct interaction between Sal B and kelch-like ECH-associated protein-1 (Keap1), an Nrf2 inhibitor. Nrf2 knock-out (Nrf2) mice and liver-specific Keap1 knockout (Hep-Keap1) mice were used to assess the role of Nrf2 and Keap1 in Sal B-mediated hepatoprotection. Mass spectrometry-based chemoproteomic analysis and mutagenesis studies were performed to identify the specific cysteine residues modified by Sal B. Molecular dynamics simulations were used to analyze conformational changes in Keap1 following Sal B binding. RESULTS: Sal B strongly activated Nrf2, and its hepatoprotective effects were significantly diminished by Nrf2 knock-out. Sal B directly bound to Keap1. In Hep-Keap1 mice, DILI was attenuated, and Sal B's protective effects were weakened. Sal B covalently modified Cys395 and Cys434 within the Keap1 double-glycine repeat (DGR) domain. Mutagenesis of these residues impaired Sal B-Keap1 interaction and abolished Nrf2 activation. Sal B's modification altered the conformation of the Keap1 kelch domain, loosening the Nrf2 binding pocket and facilitating Nrf2 activation. CONCLUSION: Sal B exerts hepatoprotective effects against DILI by activating Nrf2 through covalent modification of Keap1 at Cys395 and Cys434. These findings provide mechanistic insights into the potential of Sal B as a novel therapeutic agent for DILI.
Fupenzic acid ameliorates radiation-induced liver fibrosis by regulating RBMS1 to inhibit the cGAS-STING pathway and restore mitochondrial function.
Guo X, Liu YH, Huang BN … +4 more , Tai Y, Liu XK, Du R, Jin XJ
Phytomedicine · 2026 Jun · PMID 42314350 · Publisher ↗
BACKGROUND: Liver fibrosis, a progressive pathological condition, may culminate in cirrhosis and liver failure, with chronic inflammation and oxidative stress being key drivers. Fupenzic acid (FA), a natural triterpenoid...
BACKGROUND: Liver fibrosis, a progressive pathological condition, may culminate in cirrhosis and liver failure, with chronic inflammation and oxidative stress being key drivers. Fupenzic acid (FA), a natural triterpenoid derived from Rubus idaeus L., exhibits notable antioxidant and anti-inflammatory effects in various biological contexts. OBJECTIVE: This study sought to explore FA's therapeutic potential and underlying mechanism in mitigating radiotherapy (RT)-induced liver fibrosis. METHODS: A mouse model of hepatic fibrosis was induced through RT, with FA administered concurrently to evaluate its effects. LX-2 cells were activated with TGF-β1 to mimic fibrotic activation. The molecular mechanism was further explored using cellular thermal shift assay (CETSA) and Rbms1 overexpression experiments. RESULTS: FA treatment significantly alleviated RT-induced liver dysfunction, histological damage, and collagen deposition in mice. It also reduced serum levels of fibrotic markers and downregulated the expression of fibrosis-related genes (Col4, Fn1, Timp1) as well as proteins. Mechanistically, FA inhibited oxidative stress and inflammation. Moreover, FA preserved mitochondrial homeostasis by enhancing PINK1/Parkin-mediated mitophagy. Importantly, FA directly bound to and downregulated the RNA-binding protein RBMS1, thereby inhibiting downstream cGAS-STING signaling pathway both in vivo and in vitro. Overexpression of RBMS1 attenuated anti-fibrotic, anti-inflammatory, and pro-mitophagic effects of FA. CONCLUSION: Our research demonstrated that FA ameliorated RT-induced liver fibrosis by directly targeting RBMS1, thereby suppressing cGAS-STING pathway, mitigating inflammation as well as oxidative stress, and improving mitochondrial function. Therefore, FA emerges as a promising therapeutic candidate for preventing and treating hepatic fibrosis.
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