Phytomedicine [JOURNAL]
Sun
200 papers
Que Zui tea extract alleviates atherosclerosis via liver-vasculature-gut axis by modulating lipid metabolism, inflammation, and gut microbiota in ApoE mice.
Chen X, Cui H, Li Y … +8 more , Wang J, Fan Y, Liu Y, Cui T, Cao J, Ei-Seedi HR, Wang Z, Cheng G
Phytomedicine · 2026 Jul · PMID 42217346 · Publisher ↗
BACKGROUND: Atherosclerosis (AS), a chronic cardiovascular disease closely related to dyslipidemia and chronic inflammation, contributes to high mortality worldwide. Que Zui tea (QT) is a traditional herbal tea rich in b...
BACKGROUND: Atherosclerosis (AS), a chronic cardiovascular disease closely related to dyslipidemia and chronic inflammation, contributes to high mortality worldwide. Que Zui tea (QT) is a traditional herbal tea rich in bioactive constituents with potential health benefits. However, its anti-atherosclerotic effect and precise mechanism remain largely unknown. METHODS: UHPLC-ESI-HRMS/MS was applied to identify the chemical components of QT. The anti-atherosclerotic effects were evaluated in H₂O₂-stimulated HUVECs in vitro and high-cholesterol diet-fed ApoE mice in vivo. Serum lipid profiles, inflammatory cytokines, histopathological changes, liver transcriptomics, target protein validation, and gut microbiota composition were systematically determined. RESULTS: A total of 19 compounds were identified in the QT extract, with 6'-O-caffeoylarbutin as the dominant chemical compound. QT markedly increased the antioxidant ability (CAT, GSH, SOD) and decreased MDA accumulation in HUVECs. In ApoE mice, QT attenuated aortic atherosclerotic lesions and hepatic steatosis, reduced VCAM-1 and ICAM-1 levels, improved lipid metabolism (reducing contents of TC, TG, LDL-C, VLDL, and ox-LDL, and increasing HDL-C level), and reduced inflammation (IL-1β, IL-6, and TNF-α, and MCP-1). QT regulated lipid metabolism via PPARα/SREBP1 pathways, suppressed inflammation through the NF-κB pathway, and enhanced antioxidant capacity via Nrf2 signaling. Furthermore, QT reshaped gut microbiota structure (Defluviltaleaceae, Allobaculum, Harryflintia, Ruminococcaceae, etc.) and increased the abundance of SCFA-producing beneficial bacteria. CONCLUSION: QT exerted significant anti-atherosclerotic effects by modulating oxidative stress, lipid metabolism, inflammation, and gut microbiota. These findings supported QT as a promising natural functional product for the prevention and treatment of atherosclerosis.
Antitumor and resensitizing effects of wogonin in thyroid cancer via PDGFRB-dependent mechanisms.
Ren X, Yu F, Chen H … +3 more , Qin X, Qiu Z, Luo Q
Phytomedicine · 2026 Jul · PMID 42217345 · Publisher ↗
BACKGROUND: Wogonin, a bioactive flavonoid from Scutellaria baicalensis Georgi, exhibits broad-spectrum anticancer effects. However, whether wogonin exerts antitumor effects in thyroid cancer (TC) or reverses drug resist...
BACKGROUND: Wogonin, a bioactive flavonoid from Scutellaria baicalensis Georgi, exhibits broad-spectrum anticancer effects. However, whether wogonin exerts antitumor effects in thyroid cancer (TC) or reverses drug resistance remains unknown. METHODS: The antitumor effects of wogonin were evaluated in thyroid cancer cells and in xenograft models. RNA-sequencing, molecular docking, molecular dynamics, cellular thermal shift assay, and surface plasmon resonance were used to identify molecular targets. Lenvatinib-resistant cells were established to investigate the potential of wogonin in reversing acquired resistance. RESULTS: Wogonin inhibited TC cell proliferation, induced apoptosis and suppressed tumor growth in a dose-dependent manner. Biophysical and computational methods showed that wogonin binds to the extracellular domain of the platelet-derived growth factor receptor beta (PDGFRB), leading to its downregulation and inactivation of the PI3K/AKT pathway. Furthermore, PDGFRB overexpression was associated with acquired lenvatinib resistance, and wogonin contributed to resensitization to lenvatinib by reducing PDGFRB. CONCLUSION: Wogonin exerts remarkable antitumor effects against TC by binding to PDGFRB, leading to its downregulation, and subsequently suppressing the PI3K/AKT pathway. Furthermore, PDGFRB upregulation contributes to lenvatinib resistance in TC, while wogonin partially reverses this resistance in a PDGFRB-dependent manner.
Kushenol E alleviates sepsis-associated cognitive dysfunction via microglial indoleamine 2,3-dioxygenase 1 inhibition.
Yang Y, Lin W, Zhuo Y … +5 more , Yang J, Wei Y, Pan W, Liao Y, Yao Y
Phytomedicine · 2026 Jul · PMID 42217344 · Publisher ↗
BACKGROUND: Sepsis-associated encephalopathy (SAE) affects up to 70% of septic patients, but lacks specific therapeutic interventions. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes tryptophan degradation via the kynuren...
BACKGROUND: Sepsis-associated encephalopathy (SAE) affects up to 70% of septic patients, but lacks specific therapeutic interventions. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes tryptophan degradation via the kynurenine pathway, producing neurotoxic metabolites that drive neuroinflammation. PURPOSE: This study investigates whether kushenol E, a prenylated flavonoid from Sophora flavescens, mitigates SAE by inhibiting microglial IDO1. METHODS: Sepsis was induced by cecal ligation and puncture (CLP) in male C57BL/6J mice. Cognitive function was assessed by the novel object recognition test and the Morris water maze. Neuronal injury, neuroinflammation, and oxidative stress were evaluated by histology and biochemical assays. IDO1 expression was quantified by quantitative PCR and Western blot, and kynurenine pathway metabolites were profiled by LC-MS/MS. Kushenol E inhibition of murine IDO1 was verified in IFN-γ-stimulated BV-2 microglia. AAV9-mediated F4/80⁺ myeloid-cell-targeted IDO1 overexpression was used as an in vivo rescue strategy. RESULTS: CLP induced cognitive impairment, neuronal loss, neuroinflammation, and oxidative stress, accompanied by marked microglial IDO1 upregulation. Kushenol E preserved cognitive function, hippocampal integrity, and synaptic architecture; suppressed neuroinflammation; and limited neurotoxic kynurenine accumulation. Mechanistically, kushenol E inhibited IDO1 catalytic activity without altering its transcript or protein levels. In IFN-γ-stimulated BV-2 microglia, kushenol E suppressed kynurenine production in a concentration-dependent manner (IC = 7.38 μM), confirming direct inhibition of murine IDO1. F4/80⁺ myeloid-cell-targeted IDO1 overexpression reversed these protective effects, identifying microglial IDO1 as the principal therapeutic target. CONCLUSION: Kushenol E mitigates SAE primarily by inhibiting microglial IDO1 catalytic activity, thereby limiting neurotoxic kynurenine production. These findings nominate microglial IDO1 as a therapeutic target for SAE and support kushenol E as a lead compound for the management of cognitive sequelae in sepsis survivors.
Prenylated flavonoids from Sophora flavescens (Kushen) inhibit hepatocellular carcinoma growth by suppressing the Akt/MDM2/p53 pathway to activate mitochondrial apoptosis.
Kong S, Liao Q, Liu Y … +3 more , Tang R, Lin L, Li H
Phytomedicine · 2026 Jul · PMID 42214227 · Publisher ↗
BACKGROUND: Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and frequent development of drug resistance. Sophora flavescens, a traditional Chinese medicine, contains prenyl...
BACKGROUND: Hepatocellular carcinoma (HCC) remains a global health challenge with limited treatment options and frequent development of drug resistance. Sophora flavescens, a traditional Chinese medicine, contains prenylated flavonoids with documented antitumor potential, though their in vivo efficacy and precise molecular mechanisms against HCC remain largely unexplored. PURPOSE: This study aimed to systematically evaluate the anti-HCC activity of prenylated flavonoids in S. flavescens (PFS), identify the key bioactive constituents, and elucidate the underlying molecular mechanisms. METHODS: The chemical profile of PFS extract was characterized using UHPLC-QE-Orbitrap MS. Anti-HCC effects were assessed in vitro through cell viability, proliferation, migration, cell cycle, apoptosis, and mitochondrial function assays. An in vivo HepG2 cell-derived xenograft model was employed to evaluate tumor growth inhibition and safety. Mechanistic insights were gained via proteomics, western blotting, and in silico analysis. RESULTS: Forty-one prenylated flavonoids were identified in the extract. PFS significantly inhibited HCC cell proliferation and migration, induced cell cycle arrest, apoptosis, and mitochondrial dysfunction in vitro, and suppressed tumor growth in vivo with a favorable safety profile. Proteomic and Western blot analyses revealed that PFS mediates mitochondrial apoptosis by downregulating p-Akt and p-MDM2, upregulating p53 and NOXA, disrupting the Bax/Bcl-2 balance, and activating the cytochrome c/Caspase-3/PARP1 cascade. In silico analysis further suggested C8-prenylated flavonoids, notably (2R,3R)-5-Methoxy-7,4'-dihydroxy-8-[3,3-dimethylallyl]-flavanonol (17), Kushenol M (33), and 2'‑methoxy kushenol I (34), might be the key active components targeting the Akt/MDM2/p53 pathway. CONCLUSION: This study demonstrates that PFS inhibit HCC growth by inducing mitochondrial apoptosis via suppression of the Akt/MDM2/p53 signaling pathway. PFS represents a promising candidate for further development as a complementary therapy for HCC.
Structural characterization and inhibitory activity against silicosis of a bioactive polysaccharide from Farfarae Flos.
Nie J, Li H, Wang L … +1 more , Li Z
Phytomedicine · 2026 Jul · PMID 42214226 · Publisher ↗
BACKGROUND: Silicosis is a progressive fibrotic lung disease marked by chronic inflammation, fibroblast activation, and excessive extracellular matrix deposition. There is evidence that natural polysaccharides have the p...
BACKGROUND: Silicosis is a progressive fibrotic lung disease marked by chronic inflammation, fibroblast activation, and excessive extracellular matrix deposition. There is evidence that natural polysaccharides have the potential to attenuate the progression of silicosis. Farfarae Flos (FF), a traditional Chinese medicine, has been widely used to treat cough, asthma, and bronchitis. However, the potential effects of polysaccharides from FF on silicosis remain unknown. OBJECTIVE: This study aimed to investigate the anti-silicosis effects and underlying mechanisms of the polysaccharide from FF, as well as to characterize the structure. METHODS: A crude polysaccharide (FFP) was extracted from FF, and a homogeneous polysaccharide (FFP1) was purified from FFP by ultrafiltration. The effects of FFP against silicosis were evaluated using a silica-induced mouse model. The underlying mechanisms were explored through gut microbiota and metabolomics. The structural characteristics of FFP1 were identified using HPLC-UV, GPC-MALS-RI, ion chromatography, GC-MS, FT-IR and NMR. In addition, the anti-silicosis effects and potential mechanisms of FFP1 were further investigated in TGF-β1-induced epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transition (FMT) models in vitro. RESULTS: In this study, FFP was found to alleviate silicosis-related pathology in mice, as evidenced by histological analysis, ELISA, and immunohistochemistry. Gut microbiota and metabolomic analyses indicated that FFP mitigates silicosis by modulating gut microbiota composition and regulating the levels of phenylalanine. Furthermore, FFP1, characterized as a linear inulin-type fructan (5.891 kDa), attenuates silicosis progression by inhibiting the TGF-β1/Smad signaling pathway to suppress EMT and FMT in vitro. CONCLUSION: In conclusion, FFP exerts anti-silicosis effects in vivo by modulating gut microbiota and phenylalanine metabolism. Furthermore, FFP1, a purified inulin-type fructan, inhibits TGF-β1/Smad-mediated EMT and FMT in vitro. These findings highlight the gut-lung axis as a promising therapeutic target for silicosis prevention and treatment.
Bridging traditional knowledge and modern discovery: The role of zebrafish in anti-aging research of medicinal and edible traditional Chinese medicine.
Huang J, Li Y, Li W … +2 more , Luo Z, Liu J
Phytomedicine · 2026 Jul · PMID 42214225 · Publisher ↗
BACKGROUND: With the acceleration of global aging, anti-aging research has become a critical frontier in the life sciences. The zebrafish (Danio rerio), as a well-established model organism, offers exceptional advantages...
BACKGROUND: With the acceleration of global aging, anti-aging research has become a critical frontier in the life sciences. The zebrafish (Danio rerio), as a well-established model organism, offers exceptional advantages for anti-aging studies owing to its high genetic and physiological homology with humans, evolutionarily conserved aging mechanisms, suitability for high-throughput screening, and capacity to model telomere dynamics. Concurrently, Traditional Chinese Medicine (TCM) offers a holistic perspective on aging, attributing it to systemic imbalances such as deficiency of visceral function, qi-blood disharmony, and yin-yang imbalance. Within this framework, medicinal and edible TCM-natural substances recognized for both nutritional and therapeutic value-have shown considerable promise in mitigating aging-related processes, supported by their favorable safety profiles and historical documentation. METHODS: This review systematically collates and analyzes recent advances in the application of zebrafish as a model organism for evaluating the anti-aging efficacy of medicinal and edible TCM. Literature published up to September 2023 was retrieved from databases such as PubMed, Web of Science, and Scopus using keywords including "zebrafish," "anti-aging," "medicinal and edible herbs," and "traditional Chinese medicine." Data on aging models, mechanistic pathways, and phytochemical activities were extracted and synthesized to elucidate the synergistic potential of zebrafish and TCM in gerontological research. RESULTS: A total of 978 publications were identified using the keywords related to "anti-aging" and "medicinal and edible herbs." Subsequently, 135 relevant studies were selected for this review based on the use of zebrafish models and aging-related indicators.This review focuses on the establishment of zebrafish aging models and the evaluation of anti-aging effects of medicinal and edible traditional Chinese medicines in these models. Three major types of zebrafish aging models were identified, including chemically induced models, genetically modified models, and natural aging models, which collectively reproduced key aging-related features such as oxidative stress, DNA damage, telomere attrition, apoptosis, and cellular senescence. The medicinal and edible TCMs reviewed showed anti-aging potential mainly through enhancing antioxidant defense, modulating immune and inflammatory responses, and regulating senescence-related signaling pathways. Representative substances, including Astragalus membranaceus, Lycium barbarum, and Panax ginseng, were reported to improve aging-related phenotypes in zebrafish by increasing antioxidant enzyme activities, reducing lipid peroxidation, and modulating p53-/telomerase-associated pathways. These findings support the value of zebrafish as an efficient in vivo platform for screening and mechanistic investigation of anti-aging natural products. CONCLUSION: The integration of zebrafish models with medicinal and edible TCM research provides a powerful platform for identifying anti-aging compounds and deciphering their mechanisms of action. Despite certain limitations-such as a relatively long natural lifespan and environmental sensitivity-zebrafish offer unique advantages in telomere biology, regenerative capacity, and experimental scalability. Future studies should focus on elucidating the complex interactions among TCM compounds, optimizing model applicability, and validating findings in higher vertebrates. Through interdisciplinary collaboration, the combination of zebrafish and TCM holds promise for developing safe, effective, and naturally derived anti-aging interventions.
Renshen decoction improves myocardial energy metabolism in heart failure by regulating exosomal miR-30e-5p.
Zhou Z, Wang Q, Guo X … +7 more , Song Z, Zhang Z, Li M, Gou W, Zheng Q, Zhang M, Gong M
Phytomedicine · 2026 Jul · PMID 42214224 · Publisher ↗
BACKGROUND: Abnormal intercellular communication mediated by exosome (EXOs)-miRNAs in cardiac cells is the core pathogenic mechanism that induces myocardial energy metabolism disorders and leads to ventricular remodeling...
BACKGROUND: Abnormal intercellular communication mediated by exosome (EXOs)-miRNAs in cardiac cells is the core pathogenic mechanism that induces myocardial energy metabolism disorders and leads to ventricular remodeling in heart failure (HF). Renshen Decoction (RSD), a traditional formula, exerts significant cardioprotective effects. However, whether it inhibits ventricular remodeling in HF by regulating EXOs-miRNA-mediated intercellular communication remains unclear. OBJECTIVE: To explore the mechanism by which RSD improves myocardial energy metabolism disorders and inhibits ventricular remodeling in HF by regulating EXOs-miRNAs. METHODS: In vivo experiments were conducted to observe the inhibitory effects of RSD on myocardial energy metabolism and ventricular remodeling in HF rats. Exosomal miRNA sequencing was performed using peripheral blood samples to screen for key EXOs-miRNAs mediating the effects of RSD on HF. In vitro, cardiac fibroblasts (CFs) were stimulated with endothelin-1. CF-derived EXOs were extracted and co-cultured with cardiomyocytes (CMs) to investigate the targeted regulatory effects of RSD on the candidate CFs-EXO-miRNA. RESULTS: RSD inhibited ventricular remodeling in HF rats by ameliorating myocardial energy metabolism disorder. Peripheral blood EXOs-miRNA sequencing identified miR-30e-5p as a key miRNA targeted by RSD. In vitro experiments revealed that RSD inhibited cardiomyocyte injury induced by CFs-EXOs-miR-30e-5p Additionally, RSD suppressed the abnormally high expression of the downstream targets of miR-30e-5p, including RARβ, SIRT1, BDNF, and FTO, in HF pathology. CONCLUSION: This study is the first to demonstrate that RSD may improve the energy metabolism disorder of CMs by regulating the CFs-EXOs-miR-30e-5p-RARβ/SIRT1/BDNF/FTO pathway, thereby inhibiting HF ventricular remodeling, which may provide new ideas for the treatment of HF.
Association between senna use and outcomes in critically ill patients with hepatic failure: A propensity score-matched real-world cohort study.
Yang Q, Mo P, Wu A … +3 more , Liu Y, Guo Z, Zhao N
Phytomedicine · 2026 Jul · PMID 42214223 · Publisher ↗
BACKGROUND: Hepatic failure remains associated with substantial mortality in critically ill patients, with gut-liver axis dysfunction playing an important pathogenic role. Senna, a stimulant laxative with potential pleio...
BACKGROUND: Hepatic failure remains associated with substantial mortality in critically ill patients, with gut-liver axis dysfunction playing an important pathogenic role. Senna, a stimulant laxative with potential pleiotropic effects including gut microbiota modulation and anti-inflammatory properties, and hepatoprotective, may offer therapeutic benefits beyond bowel management. However, its impact on mortality outcomes in this population remains unclear. METHODS: This retrospective cohort study analyzed 1751 critically ill patients with hepatic failure from the MIMIC-IV database (2008-2022). Patients were stratified by senna exposure during Intensive Care Unit (ICU) stay. The primary outcome was 28-day all-cause mortality. Secondary outcomes included ventilator-free days, vasopressor-free days, and ICU-free days within 28 days. Propensity score matching (PSM) and multiple Cox regression models were employed to assess associations. Subgroup analyses explored effect modification, and dose-response relationships were also evaluated. RESULTS: Among 1751 patients (mean age 59.9 ± 15.5 years, 60.4% male), 764 (43.6%) received senna. After PSM (456 pairs), senna use was independently associated with lower 28-day mortality [adjusted: HR (hazard ratio) 0.69, 95%CI 0.58-0.82, p < 0.001]. The E-value is 1.91. This association remained robust in sensitivity analyses including PS-adjusted model (HR 0.81, 95%CI 0.68-0.96, p = 0.017), PSM cohort (HR 0.79, 95%CI 0.64-0.98, p = 0.029), and partial adjustment (HR 0.79, 95%CI 0.64-0.98, p = 0.013). A dose-response relationship was observed, with each 10 mg increase in cumulative senna dose associated with 14% lower mortality (adjusted HR 0.86, 95%CI 0.82-0.90, p < 0.001). Senna administration was associated with an increased number of ventilator-free days (adjusted β=1.38, 95%CI 0.12-2.63, p = 0.031) and vasopressor-free days (adjusted β=1.52, 95%CI 0.26-2.79, p = 0.018). Subgroup analyses revealed stronger mortality benefits in patients aged <65 years, MELD (Model for End-Stage Liver Disease) score ≥24, and APSIII (Acute Physiology Score III) score ≥74 (all p for interaction <0.05). CONCLUSIONS: In this large real-world cohort, senna use was independently associated with lower 28-day mortality with evidence of a dose-response relationship. Prospective randomized controlled trials are warranted to establish causality and inform clinical practice guidelines.
Wedelolactone alleviates rheumatoid arthritis by gut microbiota-dependent immunomodulation and p53-mediated inhibition of fibroblast-like synoviocytes.
Qiao Y, Zhang X, Wu F … +10 more , Wang Y, Wu Y, Zhang Y, Cheng W, Bu F, Miao Y, Wang Y, Huo X, Wang J, Ma X
Phytomedicine · 2026 Jul · PMID 42214222 · Publisher ↗
BACKGROUND: Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and a parallel dysbiosis of the gut microbiota. Wedelolactone (WL), a natural bioactive compound, exhibits potent anti-inflammatory and immun...
BACKGROUND: Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and a parallel dysbiosis of the gut microbiota. Wedelolactone (WL), a natural bioactive compound, exhibits potent anti-inflammatory and immunomodulatory activities; however, its therapeutic potential in RA is unknown. PURPOSE: This study aimed to evaluate the potential effect of WL on RA and explore its underlying mechanism. METHODS: The anti-arthritic activity of WL was assessed in wild-type and antibiotic‑treated (ABX) collagen‑induced arthritis (CIA) mice in vivo and in human rheumatoid-arthritis synovial fibroblasts (MH7A) cells and murine rheumatoid-arthritis fibroblast-like synoviocytes (RA-FLS) cells in vitro. Additionally, fecal microbiota transplantation (FMT), 16S rDNA sequencing, intestinal barrier integrity assays, splenic and colonic Th17/Treg analyses and targeted metabolomics of short-chain fatty acids (SCFAs) were performed to clarify its microbiota-directed actions. Finally, RNA-seq coupled with chemical inhibition and genetic knockdown with siRNA were employed to explore its effect on the hyperproliferation of synoviocytes. RESULTS: WL attenuated RA symptoms in CIA mice as evidenced by delayed disease onset, decreased joint swelling, less bone invasion and lower cumulative incidence. WL also reduced the Th17/Treg cell ratio in the spleen and colon and improved the intestinal barrier by inhibiting colonic inflammation and up-regulating tight junction proteins ZO-1 and Occludin. Concomitantly, WL reversed the RA-induced dysbiosis of gut microbiota and markedly elevated SCFAs levels, thereby restoring intestinal barrier integrity and re-establishing Th17/Treg homeostasis. FMT significantly ameliorated arthritis, further verifying the role of the gut microbiota-joint axis in the anti-arthritic effect of WL. However, FMT only partially mimicked the efficacy of WL, which was comparable to that of WL in ABX mice, indicating an additional microbiota-independent pathway. Additionally, WL directly inhibited the proliferation and migration of both MH7A and RA-FLS cells and induced G0/G1 cell cycle arrest. Transcriptomic profiling revealed that WL up-regulated p53-pathway genes including MDM2 and CDKN1A. Subsequently, pharmacologic blockade and genetic knockdown of the p53 axis abolished WL-induced decreases in cell viability and EdU positive cells and reversed the up-regulation expression of CDKN1A and HMOX1. Mechanistically, WL directly bound to p53, disrupted the p53-MDM2 interaction, suppressed p53 ubiquitination and proteasomal degradation, thereby stabilizing and upregulating p53 expression. CONCLUSION: WL mitigated CIA in mice by modulating gut microbiota-SCFAs-Th17/Treg axis and inhibiting proliferation of RA-FLS via p53 pathway. The findings provide the pre-clinical foundation for the development of WL as an anti-RA agent.
Ginseng-derived cholesterol analogues enhance pulmonary siRNA delivery and alleviate allergic asthma.
Xie L, Sun W, Jiang X … +4 more , Zhu Q, Cun D, Wu L, Yang M
Phytomedicine · 2026 Jul · PMID 42208109 · Publisher ↗
BACKGROUND: Asthma patients exhibit elevated airway mucus secretion. Small interfering RNA (siRNA) targeting the mucin MUC5AC delivered by lipid nanoparticles (LNPs) is promising but limited by low transfection efficienc...
BACKGROUND: Asthma patients exhibit elevated airway mucus secretion. Small interfering RNA (siRNA) targeting the mucin MUC5AC delivered by lipid nanoparticles (LNPs) is promising but limited by low transfection efficiency. Protopanaxadiol (PPD), protopanaxatriol (PPT), and ginsenoside Rh2 (GR2) were chosen because their dammarane skeleton preserves membrane-insertion capacity for endosomal escape, whereas bulkier multi-glycosylated ginsenosides adversely affect LNP size and stability. PURPOSE: In this study, we designed novel inhaled LNPs incorporating ginseng-derived cholesterol analogs to enhance therapeutic efficacy against asthma. METHODS: PPD and PPT were used as membrane components to formulate anti-MUC5AC siRNA-loaded LNPs (designated as DLNPs and TLNPs). Flow cytometry and confocal laser scanning microscopy (CLSM) were employed to evaluate the cellular uptake and lysosomal escape of LNPs. An asthmatic mouse model was established to assess therapeutic effects of DLNPs and TLNPs through pathological section analysis and determination of inflammatory cytokine levels. RESULTS: The data showed that these novel formulations enhanced cellular uptake by airway epithelial cells (AECs) and promoted siRNA escape from lysosomes, thereby improving pulmonary delivery efficiency. TLNPs, in particular, demonstrated superior performance. Furthermore, DLNPs and TLNPs exerted multifaceted anti‑asthmatic effects in vivo, as evidenced by significant suppression of MUC5AC overexpression in AECs, attenuation of inflammatory cell infiltration, and reduction in the secretion of the critical cytokines IL‑4 and IL‑13. CONCLUSION: Overall, our findings indicate that ginseng-derived PPD and PPT effectively enhance siRNA delivery and mitigate asthma symptoms through dual inhibition of MUC5AC overexpression and airway inflammation. These cholesterol analogs represent promising carrier materials for LNP-based pulmonary therapeutics.
Asiaticoside alleviates mesothelial cell senescence and peritoneal fibrosis by targeting macrophage-mesothelial communication in single-cell peritoneal landscape.
You Y, Wang F, Zhou Z … +6 more , Chen X, Yu M, Meng X, Jia J, Shan Y, Sheng M
Phytomedicine · 2026 Jul · PMID 42208108 · Publisher ↗
BACKGROUND: Peritoneal fibrosis (PF) is a critical factor limiting long-term peritoneal dialysis (PD). The specific composition of peritoneal cells and intercellular communication remain unelucidated in PF context. Asiat...
BACKGROUND: Peritoneal fibrosis (PF) is a critical factor limiting long-term peritoneal dialysis (PD). The specific composition of peritoneal cells and intercellular communication remain unelucidated in PF context. Asiaticoside (ASI) possesses anti-fibrotic properties, but its therapeutic effects on PD-related PF and underlying mechanisms stay unclear. PURPOSE: To investigate changes in peritoneal cell components and their interactions during PF progression. To explore the pharmacological effects and potential mechanism of ASI against PF. METHODS: A mouse PF model was induced with high-glucose peritoneal dialysis fluid (PDF). Samples of parietal peritoneum were collected for single-cell RNA sequencing. The intercellular communication network was systematically characterized within the PF microenvironment. Immunohistochemistry, immunofluorescence, western blotting, qRT-PCR, and ELISA were conducted to elucidate the specific anti-fibrotic mechanisms of ASI. RESULTS: The single-cell RNA sequencing atlas of PD-induced PF comprises 57,032 single cells classified into seven distinct cell types. Insulin-like growth factor 1 (IGF1) signaling was dysregulated in PF between macrophages and mesothelial cells and regulated mesothelial cell senescence. The accumulation of senescent mesothelial cells and their senescence-associated secretory phenotype (SASP) promoted inflammaging and thereby exacerbated PF. IGF1 supplementation with M2-Mφ supernatants or exogenous IGF1 alleviated mesothelial cell senescence and decreased fibrotic responses in PF mice. Treatment with ASI alleviated mesothelial cell senescence and prevented PF in vivo. ASI inhibited mesothelial cell senescence by enhancing IGF1 signaling in macrophages-mesothelial communication. CONCLUSION: ASI inhibited mesothelial cell senescence via macrophage/IGF1 axis to alleviate PF in single-cell peritoneal landscape. These findings highlight the potential of ASI as a therapeutic agent against PF.
Licochalcone B alleviates atherosclerosis by inhibiting endothelial inflammation via targeting the KEAP1/NRF2/NF-κB signalling pathway.
Liao ZF, Zhou WQ, Du SQ … +14 more , Liu XM, Yao J, Din ZU, Shi ZC, Cai MY, Wang SH, Tang XB, Ding ZY, Li XR, Wu ZG, Xu S, Qi Y, Luo H, Xiong XD
Phytomedicine · 2026 Jul · PMID 42208107 · Publisher ↗
BACKGROUND: Atherosclerosis is a chronic inflammatory disorder of the arterial subendothelium that remains a major clinical challenge. Licochalcone B (LCB), a licorice-derived flavonoid, has been documented to display an...
BACKGROUND: Atherosclerosis is a chronic inflammatory disorder of the arterial subendothelium that remains a major clinical challenge. Licochalcone B (LCB), a licorice-derived flavonoid, has been documented to display anti-inflammatory effects; however, its therapeutic potential for atherosclerosis remains unknown. PURPOSE: To evaluate the efficacy of LCB against atherosclerosis and to uncover the mechanisms involved. STUDY DESIGN AND METHODS: To establish an atherosclerosis model, ApoE mice were fed a high-fat diet, after which they received treatment with either LCB at two different doses or simvastatin for 8 weeks. Therapeutic efficacy was evaluated via histological analysis. In vitro studies employing transcriptome sequencing, Western blotting, immunofluorescence, cellular thermal shift assay, surface plasmon resonance, molecular docking, and RNA interference were conducted to examine the anti-inflammatory mechanisms of LCB in endothelial cells. RESULTS: LCB treatment significantly attenuated atherosclerotic progression, as evidenced by reduced plaque area and increased plaque stability, along with suppression of endothelial inflammation in ApoE mice. Mechanistically, LCB directly targeted KEAP1 in endothelial cells, promoting its autophagic degradation. This event initiated an NRF2-dependent antioxidant response, subsequently suppressed NF-κB p65 phosphorylation at Ser276, and ultimately downregulated VCAM1 and ICAM1 in inflamed endothelial cells. CONCLUSION: This study offers the first demonstration that LCB attenuates atherosclerosis through the suppression of endothelial inflammation by targeting the KEAP1/NRF2/NF-κB axis. Notably, LCB exhibited no hepatotoxicity or nephrotoxicity, underscoring its suitability as a safe pharmacological agent for atherosclerotic cardiovascular disease.
An-Gong-Niu-Huang-Wan ameliorates neurovascular uncoupling and facilitates recovery after cerebral ischemic stroke by mediating P2X7 receptor inhibition.
Zhang X, Zhou H, Pei J … +8 more , Xu R, Xue L, Zhang Y, Qi P, Zhang X, Fu L, Zhang C, Cui L
Phytomedicine · 2026 Jul · PMID 42208106 · Publisher ↗
BACKGROUND: Neurovascular uncoupling is a critical yet underrecognized pathological mechanism that exacerbates neurological injury after cerebral ischemic stroke. An-Gong-Niu-Huang-Wan (AGNHW), a well-established traditi...
BACKGROUND: Neurovascular uncoupling is a critical yet underrecognized pathological mechanism that exacerbates neurological injury after cerebral ischemic stroke. An-Gong-Niu-Huang-Wan (AGNHW), a well-established traditional Chinese formula, has been clinically utilized for stroke management for over two centuries owing to its multi-target neuroprotective properties. However, its potential to ameliorate impaired neurovascular coupling following ischemic insult remains largely unexplored. PURPOSE: This study aimed to elucidate the therapeutic mechanism of AGNHW in restoring neurovascular coupling, with a focus on the purinergic P2X7 receptor (P2X7R) signaling pathway. METHODS: A distal middle cerebral artery occlusion model was induced in male C57BL/6 mice. AGNHW was administered intragastrically 1 hour post-occlusion. Cortical neurovascular coupling was evaluated using laser speckle contrast imaging during whisker stimulation. Functional recovery was assessed via gait analysis and grip strength, while tissue injury was examined through hematoxylin and eosin staining. Neuronal activity, monitored in rAAV2/9-CaMKIIα-GCaMP6s mice, and arterial hemodynamics were visualized using two-photon microscopy during functional hyperemia. RNA sequencing was employed to identify potential mechanistic targets of AGNHW, followed by molecular biology techniques to investigate the role of purinergic signaling, particularly P2X7R-mediated regulation of neurovascular coupling. RESULTS: Compared with the control group, AGNHW treatment significantly enhanced the cerebral blood flow response and increased the area under the curve during whisker stimulation, accompanied by alleviated neuronal damage and improved motor function-reflected by prolonged stance time and elevated peak pressure in the affected forelimb and enhanced grip strength. AGNHW also markedly increased the signal intensity of calcium activity (ΔF/F₀) following ischemia. Furthermore, AGNHW improved arterial hemodynamics by promoting arterial dilation, increasing red blood cell velocity, and elevating red blood cell flux during functional hyperemia. It also ameliorated blood-brain barrier integrity and upregulated the expression of tight junction proteins (ZO-1, occludin, claudin5). Mechanistically, AGNHW downregulated the genes expression of P2rx7, P2ry12, and Adora2a, and inhibited P2X7R activation by reducing ATP release, thereby inhibited inflammatory cell infiltration and alleviating the secretion of inflammatory mediators such as IL-1β, IL-18, and TNF-α. Notably, activation of P2X7R signaling abolished the protective effects of AGNHW on cerebral blood flow response and blood-brain barrier integrity. CONCLUSIONS: AGNHW attenuated neurovascular uncoupling and improved cerebral blood flow response and neuronal activity during whisker stimulation after cerebral ischemia, mediated by inhibition of the P2X7R-driven purinergic-inflammatory cascade. These findings elucidated a mechanism through which AGNHW preserves neurovascular function.
Erzhi pill enhances methotrexate efficacy in rheumatoid arthritis bone homeostasis via activation of the IDO1-KYN-AhR pathway.
Li X, Liu X, Ye Q … +7 more , Wang S, Xi X, Jiang J, Mao X, Fang M, Jin W, Xiao C
Phytomedicine · 2026 Jul · PMID 42208105 · Publisher ↗
Progressive joint destruction and systemic bone loss are key factors contributing to disability and secondary osteoporosis in rheumatoid arthritis (RA). However, current clinical drugs, including first-line methotrexate...
Progressive joint destruction and systemic bone loss are key factors contributing to disability and secondary osteoporosis in rheumatoid arthritis (RA). However, current clinical drugs, including first-line methotrexate (MTX), provide limited bone protection. Enhancing the regulatory effect of MTX on RA bone homeostasis through combination with traditional Chinese medicine (TCM) may offer a new perspective for RA treatment. This study investigated whether Erzhi pill (EZP), a kidney-tonifying TCM formula, enhances MTX efficacy in regulating bone homeostasis in RA via the IDO1-KYN-AhR signaling pathway. Using primary osteoblast/osteoclast models and a kidney deficiency collagen-induced arthritis (KD-CIA) rat model, we demonstrated that the MTX+EZP combination was superior to MTX monotherapy in promoting osteoblast differentiation/function, suppressing osteoclastogenesis, and mitigating bone destruction and loss in KD-CIA rats. These effects were associated with the restoration of suppressed IDO1-KYN-AhR signaling activity. Furthermore, siRNA-mediated knockdown or pharmacological inhibition of IDO1 or AhR reversed the regulatory effects of MTX+EZP on osteoblast-osteoclast differentiation/function and its bone-protective actions in KD-CIA rats. Finally, salidroside and ferulic acid were identified as the potential active compounds in EZP responsible for synergizing with MTX. In summary, our findings demonstrate that EZP enhances the efficacy of MTX in regulating RA bone homeostasis by activating the IDO1-KYN-AhR signaling pathway, representing a promising integrative strategy for managing RA-induced bone metabolism disorders.
Buxus alkaloid KBA01 targets Valosin-containing protein to inhibit colorectal cancer progression via the p53-Wnt/β-catenin axis.
Wang J, Su Y, Zhang L … +6 more , Mou H, Wu W, Xia Y, Yu F, Yang F, Zhang J
Phytomedicine · 2026 Jul · PMID 42208104 · Publisher ↗
BACKGROUND: Mutant p53 is closely associated with tumor proliferation and metastasis, making an attractive therapeutic target in cancer treatment. Buxus alkaloids exhibit antibacterial and antiviral properties, however,...
BACKGROUND: Mutant p53 is closely associated with tumor proliferation and metastasis, making an attractive therapeutic target in cancer treatment. Buxus alkaloids exhibit antibacterial and antiviral properties, however, research into their antitumor potential remains limited. KBA01, a triterpenoid alkaloid isolated from the leaves and stems of Buxus bodinieri Levl, activates the p53 signaling pathway in colorectal cancer cells; however, its drug targets and mechanism of action remain unclear. PURPOSE: To identify the molecular target of KBA01 and elucidate how it suppresses tumor growth through activation of the p53 signaling pathway. METHODS: Activity-based protein profiling (ABPP) assay was performed to identify the potential target of KBA01. Wound healing, cell colony formation and transwell assays were conducted to elucidate the effects of KBA01 on cell proliferation, migration, and invasion. Western blot, RT-qPCR, Immunoprecipitation (IP), Co-Immunoprecipitation (Co-IP), Electrophoretic mobility shift assay (EMSA), Chromatin immunoprecipitation (ChIP), and Luciferase reporter assays were applied to investigate the effects of KBA01 on p53 function. The colorectal cancer xenograft experiment was performed to evaluate the in vivo anticancer activity. RESULTS: KBA01 targets Valosin-containing protein (VCP), reducing its interaction with p53 R273H and thereby promoting the ubiquitination and degradation of mutant p53. Consequently, KBA01 disrupts the dominant negative effect of mutant p53. KBA01 elevated the p53 downstream targeted genes p21 and PUMA mRNA and protein levels, thereby activating the p53 signaling pathway and ultimately inhibiting tumor growth and metastasis in vitro. In addition, KBA01 inhibits the Wnt/β-catenin pathway in tumor cells harboring mutant p53. Further in vivo studies demonstrated that KBA01 significantly suppressed tumor growth in colorectal cancer xenograft models by inducing mutant p53 depletion and reactivating p53 downstream target genes, achieving a tumor inhibition rate of 61.39%. CONCLUSION: These findings identify VCP as the molecular target of KBA01 and suggest that KBA01 selectively promotes the degradation of mutant p53 R273H, thereby alleviating its dominant-negative effect and restoring p53 signaling. Collectively, this study broadens the potential pharmacological applications of Buxus alkaloids and supports the further investigation of KBA01 as a lead compound for mutant p53-targeted therapy.
Integrative single-cell analysis reveals Bu-Shen-Huo-Xue Formula rescues iron-overloaded ovarian function via rewiring IFN-γ/JAK/STAT/CXCL10-driven immune-stromal interactions and BNIP3-mediated mitophagy in endometriosis.
Ni Z, Zhao Q, Li Y … +9 more , Mei S, Yu J, Ding J, Liang X, Sun S, Wang Y, Cheng W, Zhou W, Yu C
Phytomedicine · 2026 Jul · PMID 42208103 · Publisher ↗
BACKGROUND: Ovarian endometriosis (OE) is a leading cause of female infertility. Our previous work identified iron overload-driven oxidative stress and mitochondrial dysfunction in granulosa cells as key pathogenic featu...
BACKGROUND: Ovarian endometriosis (OE) is a leading cause of female infertility. Our previous work identified iron overload-driven oxidative stress and mitochondrial dysfunction in granulosa cells as key pathogenic features, yet the mechanism of the clinically effective Bu-Shen-Huo-Xue Formula (BHF) remains unclear. PURPOSE: To determine how BHF mitigates OE-associated ovarian injury and infertility, and to identify key bioactive constituents and molecular targets. METHODS: An OE mouse model was treated with BHF to evaluate pelvic adhesions, lesion volume, fibrotic remodeling, and reproductive outcomes. Integrated single-cell RNA sequencing (scRNA-seq) and Stereo-seq were used to define iron overload-associated ovarian niches. Granulosa cell mitochondrial function, ROS, senescence, and BNIP3-PINK1/Parkin-dependent mitophagy were assessed. Serum pharmacochemistry was performed to identify BHF constituents and validate target engagement. RESULTS: BHF reduced pelvic adhesions, lesion volume, and fibrotic remodeling, and improved reproductive outcomes in OE mice. Iron overload established a corpus luteum-proximal immuno-fibrotic niche characterized by interferon programs and JAK-STAT activation; BHF attenuated this niche by suppressing CXCL10-mediated immune recruitment and fibroblast activation. At the follicular level, iron overload induced excessive BNIP3-PINK1/Parkin-dependent mitophagy, resulting in mitochondrial dysfunction, ROS accumulation, senescence, and stress-associated metabolic reprogramming; BHF restored mitochondrial homeostasis and alleviated these alterations. Ononin was identified as a major circulating constituent that directly binds BNIP3 and inhibits iron-induced mitophagy, preserving granulosa-cell function. CONCLUSION: BHF acts as a multi-target intervention that protects against OE-associated ovarian injury by dampening iron overload-linked immuno-fibrotic remodeling and restraining BNIP3-dependent mitophagy; ononin is a BNIP3-targeting bioactive component with therapeutic potential.
Chinese medicine Sheng Jing Decoction alleviates oligoasthenospermia by modulating PI3K/Akt and MAPK signaling pathways.
Gao S, Yun D, Zhu Z … +7 more , Chen Z, Ren H, Wang L, Bu T, Zhao Y, Li Z, Sun F
Phytomedicine · 2026 Jul · PMID 42208102 · Publisher ↗
BACKGROUND: Oligoasthenospermia (OAT), a major cause of male infertility, is characterized by reduced sperm count and motility, yet effective treatments remain limited. Sheng Jing Decoction (SJD), a clinically used tradi...
BACKGROUND: Oligoasthenospermia (OAT), a major cause of male infertility, is characterized by reduced sperm count and motility, yet effective treatments remain limited. Sheng Jing Decoction (SJD), a clinically used traditional Chinese multi-herbal formulation developed by our team, has shown potential in improving sperm quality in animal models, but its molecular mechanisms have not been systematically elucidated. METHODS: An OAT mouse model was established via intraperitoneal injection of triptolide (TP). SJD was administered by oral gavage for one month, beginning two days after TP treatment initiation. The chemical composition of SJD was characterized by ultra-high-performance liquid chromatography. Sperm concentration, motility, and testicular spermatogenic progression were evaluated with computer-assisted semen analysis (CASA) and hematoxylin and eosin (HE). Transcriptomic analysis was performed on testicular tissue, and apoptosis, oxidative stress, and inflammation were assessed. Key molecules in the PI3K/Akt and MAPK pathways were quantified using Western blot and RT-qPCR. RESULTS: SJD significantly improved sperm concentration, motility, and overall quality, including the restoration of spermatogenic progression compared to the TP-treated group. Transcriptomic analysis revealed differentially expressed genes and enriched pathways related to spermatogenesis and sperm motility, consistent with phenotypic improvements. Mechanistically, SJD alleviated TP-induced testicular apoptosis, oxidative stress, and inflammation. Furthermore, SJD acts through the MAPK and PI3K/Akt signaling pathways, both of which are regulated by Ras as a common upstream regulator. CONCLUSION: SJD effectively alleviates TP-induced OAT in mice by reducing testicular apoptosis, inflammation, and oxidative stress, as well as by restoring spermatogenesis, likely through modulation of the PI3K/Akt and MAPK signaling pathways. These findings provide mechanistic support for the potential application of SJD as a complementary therapeutic strategy for male infertility, especially that caused by environmental factors.
Bilobalide attenuates Salmonella typhimurium virulence by repressing the quorum sensing and type III secretion system effectors.
Wang R, Hui H, Zhang X … +5 more , Song Y, Yang J, Wu S, Peng J, Li X
Phytomedicine · 2026 Jul · PMID 42208101 · Publisher ↗
BACKGROUND: Salmonella typhimurium is a major food-borne pathogen whose virulence is regulated by quorum sensing (QS) and the type III secretion system (T3SS). The rise of antibiotic resistance highlights the need for an...
BACKGROUND: Salmonella typhimurium is a major food-borne pathogen whose virulence is regulated by quorum sensing (QS) and the type III secretion system (T3SS). The rise of antibiotic resistance highlights the need for anti-virulence strategies targeting bacterial communication. Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, has antimicrobial potential, but its role in QS regulation remains unclear. This study investigates how bilobalide modulates QS and virulence in S. typhimurium to support the development of anti-infective strategies. PURPOSE: This study aimed to elucidate the molecular mechanism by which bilobalide attenuates S. typhimurium virulence, including biofilm formation, motility, and cytotoxicity. Additionally, the study evaluated bilobalide's potential as a QS inhibitor and adjunct to antibiotic therapy. METHODS: Phenotypic assays assessed the effects of bilobalide on S. typhimurium biofilm formation, motility, and cytotoxicity. RNA sequencing (RNA-seq) and RT-qPCR analyses identified differentially expressed genes after bilobalide treatment. Microscale thermophoresis (MST), molecular docking, and molecular dynamics simulations characterised the interaction between bilobalide and QseB. Electrophoretic mobility shift assays were used to determine whether bilobalide affected QseB-DNA binding. The combined antibacterial effects of bilobalide and antibiotics were evaluated using microdilution assays. In vivo efficacy was tested using a mouse infection model. RESULTS: Bilobalide significantly inhibited biofilm formation, motility, and T3SS gene expression in S. typhimurium without affecting bacterial growth. RNA-seq revealed broad transcriptional changes, including downregulation of virulence-related genes. MST confirmed that bilobalide binds to the REC domain of QseB with high affinity, particularly at residues Leu11 and Phe103. Bilobalide reduced QseB's ability to bind the promoters of luxS and T3SS effectors. In mice, bilobalide treatment alleviated S. typhimurium-induced inflammation, restored intestinal barrier proteins, and enhanced antibiotic efficacy, indicating strong anti-virulence and therapeutic value. CONCLUSION: Bilobalide suppresses S. typhimurium virulence by binding to and inhibiting the response regulator QseB, thereby disrupting quorum sensing and T3SS system. These findings suggest that bilobalide is a promising natural anti-virulence agent and potential compound for developing novel anti-infective therapies.
Therapeutic potential of Amentoflavone against myostatin for skeletal muscle atrophy treatment: An in silico, in vitro, and in vivo study.
Lim JH, Ahmad SS, Lee EJ … +2 more , Choi JM, Choi I
Phytomedicine · 2026 Jul · PMID 42190600 · Publisher ↗
BACKGROUND: Myostatin (MSTN) negatively regulates skeletal muscle (SM) growth, and its over activity suppresses myogenic differentiation, promoting muscle atrophy and aging. Amentoflavone (AMF), a biflavonoid from Ginkgo...
BACKGROUND: Myostatin (MSTN) negatively regulates skeletal muscle (SM) growth, and its over activity suppresses myogenic differentiation, promoting muscle atrophy and aging. Amentoflavone (AMF), a biflavonoid from Ginkgo biloba, possesses anti-atrophy effects. AMF has anti-inflammatory, antioxidant, antitumor, and anti-viral properties. The effect of AMF on SM atrophy and myoblast differentiation has not been explained. PURPOSE: This study was conducted to evaluate the effects of AMF on promoting muscle growth and to elucidate its underlying mechanisms. METHODS: AMF was screened against MSTN using molecular docking and further validated by 100-ns molecular dynamics (MD) simulations. In vitro experiments used C2C12 myoblasts and human muscle satellite cells (MSCs) to assess the AMF effect on the proliferation and differentiation. In vivo, a dexamethasone-induced mouse model of muscle atrophy was used to examine the effect of AMF on muscle mass, fibre morphology, and function. RESULTS: In silico analyses revealed strong AMF-MSTN binding and a stable complex confirmed by MD simulation (100 ns) and cellular thermal shift assay. AMF enhanced myogenic differentiation in C2C12 and human MSCs, increasing MYH and MYOG gene and protein expression while reducing MSTN and phosphorylated SMAD levels. In dexamethasone-induced atrophic C2C12 and human MSCs, AMF restored myogenic markers and suppressed MSTN expression and signaling. In atrophic mice, AMF prevented weight and muscle loss; improved fiber cross-sectional area, strength, and endurance; decreased MSTN, Atrogin-1, MuRF1; and activated MYH and AKT/mTOR pathways. CONCLUSION: AMF interacts with MSTN, inhibiting its downstream signaling, promoting myogenic differentiation, and alleviating muscle atrophy, highlighting its potential as a natural therapeutic for muscle-wasting conditions. Through computational modeling, MD simulations, and experimental validation, AMF demonstrates strong binding to MSTN, with confirmed efficacy in both in vitro and in vivo studies.
Kaempferol functionally reprograms CD47 signaling to promote cytoprotection and attenuate oxeiptosis in severe acute pancreatitis.
Tian Y, Zhang Y, Gao Q … +5 more , Zhang P, You L, Huang R, Zhang A, Wen E
Phytomedicine · 2026 Jul · PMID 42184499 · Publisher ↗
BACKGROUND: Severe acute pancreatitis (SAP) lacks targeted therapies, and massive loss of functional pancreatic acinar cells (PAC) drives mortality. Kaempferol (KA) possesses well-established anti-inflammatory and cytopr...
BACKGROUND: Severe acute pancreatitis (SAP) lacks targeted therapies, and massive loss of functional pancreatic acinar cells (PAC) drives mortality. Kaempferol (KA) possesses well-established anti-inflammatory and cytoprotective activities and is derived from herbal medicinal plants, but its direct molecular targets and mechanism of action in SAP remain undefined. PURPOSE: To evaluate the protective effects of KA against SAP and to elucidate its molecular mechanism of specific action, with a focus on identifying the direct cellular target through which KA exerts its cytoprotective effects. STUDY DESIGN: Gain‑/loss‑of‑function in vitro and PAC‑specific CD47 SAP mouse models, combined with multi‑omics screening and biophysical assays. METHODS: CD47 manipulation (siRNA/overexpression) was performed in primary PACs and cell lines, combined with WT/CD47/Mist1‑CD47‑iOE (PAC‑specific) mouse models. Network pharmacology, transcriptomics and proteomics were integrated to screen and validate KA's protective effects. Computational‑experimental approaches (molecular docking/dynamics, CETSA, SPR, co‑IP, pharmacological epistasis) characterized KA's allosteric modulation of CD47 signaling. RESULTS: CD47 was upregulated in SAP; its knockout reduced PAC death via KEAP1/PGAM5/AIFM1-driven oxeiptosis. KA reduced PAC death across genotypes, afforded no extra benefit in CD47-KO, and was not overridden by CD47‑OE. Mechanistically, KA allosterically binds CD47 ectodomain, stabilizes the CD47‑ UBQLN1 complex, and redirects signaling from Gαi‑mediated death to Gβγ/ ERK/NRF2‑mediated survival. ERK inhibition attenuated KA's protection. KA's action was CD47‑dependent. CONCLUSION: This study identifies anti-oxeiptosis as a novel pharmacological activity of KA in SAP. This is achieved through allosteric modulation of CD47, redirecting its signaling from death‑promoting to a protective axis via activating Gβγ/ERK/NRF2 to suppress oxeiptosis. These findings reveal the CD47‑oxeiptosis axis as a therapeutic target and position KA as a promising candidate for SAP therapy, adding a new mechanistic dimension to KA's known pharmacological profile.
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