Phytomedicine [JOURNAL]
Sun
200 papers
CRISPR screen identifies MAP2K3 as a key target for oleuropein to alleviate deoxynivalenol-induced hepatic injury.
Yang Y, Wu Y, Xu X … +3 more , Ihsan A, Han L, Wang X
Phytomedicine · 2026 Aug · PMID 42275882 · Publisher ↗
INTRODUCTION: Deoxynivalenol (DON), a widely prevalent mycotoxin in temperate climates, causes significant hepatic injury upon the consumption of contaminated cereals. However, the key targets and mechanisms underlying D...
INTRODUCTION: Deoxynivalenol (DON), a widely prevalent mycotoxin in temperate climates, causes significant hepatic injury upon the consumption of contaminated cereals. However, the key targets and mechanisms underlying DON-induced inflammatory hepatic injury remain unclear, thus hindering the development of targeted therapeutics. OBJECTIVES: This study aimed to identify the key host targets mediating DON-induced inflammatory hepatic injury and its underlying molecular mechanism, as well as to discover potential therapeutic agents for alleviating this damage. METHODS: We established a J774A.1-CRISPR-Cas9 whole-genome knockout library to screen for host genes essential for DON-induced apoptosis. Structure-based virtual screening was employed to identify MAP2K3 inhibitors, and the mechanism of oleuropein (Ole) action was explored using both in vivo and in vitro models. RESULTS: CRISPR screening revealed that MAP2K3 is crucial for DON-induced apoptosis. Mechanistically, MAP2K3 mediates inflammatory hepatic injury by activating the p38/p53/caspase-8/caspase-9/caspase-3 pathway. Virtual screening identified Ole as a direct MAP2K3 inhibitor, which binds to key amino acid residues (Lys149, Ser194, Tyr230). Ole effectively inhibited DON-induced hepatic damage in vitro. In the DON-induced murine hepatitis model, Ole demonstrated robust therapeutic effects against DON-induced hepatitis, and its efficacy was superior to that of N-acetylcysteine (NAC). CONCLUSION: This study demonstrates that MAP2K3 is a key target mediating DON-induced inflammatory hepatic injury and confirms oleuropein (Ole) as a potential therapeutic agent. Together, these findings advance our understanding of the underlying mechanisms and propose a new treatment strategy.
Shuxuening injection ameliorates poststroke cognitive impairment by regulating multiple cell death pathways.
Lv J, Tao X, Wu Y … +8 more , Chen X, Lv L, Guo F, Zhang L, Zhang X, Gan G, Lu Y, Dong D
Phytomedicine · 2026 Aug · PMID 42275881 · Publisher ↗
BACKGROUND: Poststroke cognitive impairment (PSCI) frequently occurs after ischaemic stroke (IS). Despite its widespread clinical application in treating ischaemic cardio-cerebrovascular diseases, the effect of Shuxuenin...
BACKGROUND: Poststroke cognitive impairment (PSCI) frequently occurs after ischaemic stroke (IS). Despite its widespread clinical application in treating ischaemic cardio-cerebrovascular diseases, the effect of Shuxuening injection (SXNI) on PSCI is unknown. METHODS: The therapeutic effects of SXNI were assessed with a modified neurological severity score (mNSS), Y-maze tests, cerebral infarction volume measurements, and histopathological examinations. To identify key targets and pathways involved in SXNI treatment, we conducted integrated multiomics studies combining transcriptomic and proteomic analyses, supplemented by biochemical assays and transmission electron microscopy (TEM). Validation was performed through qPCR, enzyme-linked immunosorbent assay (ELISA), immunofluorescence and Western blotting analysis. Finally, the components in SXNI were analyzed both qualitatively and quantitatively using ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) and LC-MS/MS. RESULTS: Integrated multiomics analyses suggested that SXNI may exert therapeutic effects on PSCI through multiple signalling pathways. By modulating key pathways linked to oxidative stress, immune, and inflammatory response signaling, SXNI thereby demonstrated a significant role in acute ischaemic stroke (AIS) pathogenesis. Building on monotherapy investigations, we subsequently explored the therapeutic potential of combining SXNI with Edaravone (EDA). CONCLUSIONS: SXNI suppresses pyroptotic and oxeiptotic signaling in the ischaemic brain by concurrently regulating the HIF-1α/NLRP3 and KEAP1/PGAM5/AIFM1 axes. By targeting ROS mediated death, SXNI effectively mitigates injury and offers a promising therapeutic strategy for AIS.
UGP-RAP: A DI-QDa-MS powered deep learning platform for automated identification of ultrafine granular powders.
Huang F, Li ZW, Wang JW … +10 more , Zhang MJ, Xia TY, Wang GY, Zhang DD, Liu XK, An YL, Zhang QL, Peng LH, Qiao WL, Guo DA
Phytomedicine · 2026 Aug · PMID 42275880 · Publisher ↗
BACKGROUND: The chemical composition of herbal-derived ultrafine granular powders is highly complex, and conventional identification methods often struggle to achieve an effective balance between analytical throughput an...
BACKGROUND: The chemical composition of herbal-derived ultrafine granular powders is highly complex, and conventional identification methods often struggle to achieve an effective balance between analytical throughput and identification reliability. PURPOSE: This study aimed to develop a rapid automated platform for the intelligent identification of ultrafine granular powders using direct infusion QDa mass spectrometry (DI-QDa-MS) and cosine similarity-enhanced deep learning. METHODS: An automated identification platform, termed Ultrafine Granular Powder Rapid Automated Identification Platform (UGP-RAP), was developed by integrating one-dimensional convolutional neural network (1D-CNN), full-ion cosine similarity, and binary cosine similarity within a unified analytical framework. Samples were analyzed by DI-QDa-MS, with per-injection analysis time of approximately 2 min. For the binary cosine similarity approach, the top 200 and 250 most intense peaks in the positive and negative ion modes, respectively, were selected to optimize discriminative performance. A dataset of 530 batches was constructed and split into training, validation, and test sets for model development. External validation was conducted on 63 commercially sourced batches. RESULTS: UGP-RAP achieved an overall identification accuracy of 98.41% in external validation, with a prediction confidence of 100%. Across all datasets, the 1D-CNN model consistently outperformed conventional KNN and SVM models, while both cosine similarity-based approaches demonstrated strong discriminative capability in positive and negative ion modes. Through multi-model integration and consensus-based decision strategies, UGP-RAP enabled a high-throughput, low-manual-intervention automated identification workflow with intuitive visualization of prediction results. Overall, the platform provides an efficient and reliable analytical solution for the rapid identification and quality control of ultrafine herbal powders, demonstrating considerable potential for routine analytical applications.
Quercetin targets BCAT1 to potentiate CD8 T cell immunity by rewiring branched-chain amino acid metabolism against colorectal cancer metastasis.
Wang C, Xu Y, Ding P … +10 more , Ding Y, Zheng L, Li T, Cheng S, Zhang C, Ji F, Liu X, Chen K, Gu G, Lu X
Phytomedicine · 2026 Aug · PMID 42275879 · Publisher ↗
Colorectal cancer (CRC) metastasis is a major cause of cancer‑related death, highlighting the need for therapies that target immune‑metabolic pathways. Here, we show that quercetin inhibits CRC progression via dual actio...
Colorectal cancer (CRC) metastasis is a major cause of cancer‑related death, highlighting the need for therapies that target immune‑metabolic pathways. Here, we show that quercetin inhibits CRC progression via dual actions: directly suppressing tumor cell growth and migration, while systemically reinvigorating CD8 T cell mediated immunity. In vitro, quercetin potently inhibited CRC cell proliferation, migration, and survival. In an experimental lung metastasis mouse model, quercetin enhanced the effector function of CD8 T cells, as evidenced by increased production of Granzyme B, Perforin, and IFN-γ in metastases, blood, and tumor-draining lymph nodes. Metabolomic profiling uncovered a pronounced remodeling of branched-chain amino acid (BCAA) metabolism following quercetin intervention. Screening via the HERB database identified BCAA transaminase 1 (BCAT1) as a candidate target, confirmed by molecular docking and surface plasmon resonance (SPR). Importantly, the combination of oral leucine and quercetin produced a synergistic effect, significantly boosting CD8 T cell cytotoxicity and dramatically reducing the lung metastatic burden. Taken together, these data identify BCAT1 as a direct target of quercetin and elucidate a resultant immunometabolic circuit that bolsters CD8 T cell function, providing a rationale for targeting this pathway in advanced CRC.
β-mangostin triggers ER stress-mediated mitochondrial dysfunction to induce apoptosis in colorectal cancer.
Ma M, Tang W, Zhang A … +5 more , Gu X, Zhou Y, Sheng Q, Xie T, Sui X
Phytomedicine · 2026 Aug · PMID 42275878 · Publisher ↗
BACKGROUND: β-Mangostin (BM), a bioactive xanthone derived from the pericarp of Garcinia mangostana L., exhibits antitumor potential; however, its efficacy and mechanisms in colorectal cancer (CRC) remain unclear. PURPOS...
BACKGROUND: β-Mangostin (BM), a bioactive xanthone derived from the pericarp of Garcinia mangostana L., exhibits antitumor potential; however, its efficacy and mechanisms in colorectal cancer (CRC) remain unclear. PURPOSE: To evaluate the antitumor activity of BM against CRC and elucidate its underlying mechanisms. METHODS: The anticancer effects on HCT116 and SW480 cells were evaluated using the CCK-8 assay and xenograft tumor model in vivo. Apoptosis, cell cycle distribution, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and Ca²⁺ dynamics were analyzed via flow cytometry and fluorescence imaging. The molecular mechanisms were investigated using RNA sequencing and Western blotting. RESULTS: BM significantly inhibited CRC cell proliferation and induced apoptosis in a dose-dependent manner, accompanied by G phase arrest. Mechanistically, BM triggered pronounced endoplasmic reticulum (ER) stress, leading to intracellular Ca²⁺ dysregulation and mitochondrial Ca²⁺ overload. This resulted in mitochondrial dysfunction, characterized by MMP collapse, ATP depletion, excessive ROS generation, and subsequent DNA damage. Notably, CHOP knockdown and Ca²⁺ chelation significantly attenuated BM-induced apoptosis, confirming the critical involvement of ER stress-mediated Ca²⁺ signaling. In vivo, BM markedly suppressed tumor growth without observable systemic toxicity. Immunohistochemical analysis further demonstrated increased ER stress and apoptosis markers and reduced proliferation in tumor tissues. CONCLUSION: BM exerts potent antitumor effects in CRC by activating an ER stress-mediated mitochondrial dysfunction axis involving Ca²⁺ imbalance and oxidative stress, highlighting its potential as a promising therapeutic candidate.
Ergothioneine alleviates hepatic steatosis by modulating PCYT2 to restore the phosphatidylethanolamine-ACOT8 homeostasis.
Ye R, Wang Y, Wang K … +7 more , Huang N, Liu G, Gao D, Li X, Yang M, Wang J, Chen C
Phytomedicine · 2026 Aug · PMID 42275877 · Publisher ↗
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning global health burden with limited pharmacological options. Ergothioneine (EGT), a naturally occurring antioxidant, shows potential hepatoprote...
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning global health burden with limited pharmacological options. Ergothioneine (EGT), a naturally occurring antioxidant, shows potential hepatoprotective effects; however, the exact mechanisms by which EGT regulates lipid metabolism in NAFLD remain elusive. PURPOSE: This study aimed to investigate the therapeutic efficacy and potential mechanisms of EGT in high-fat diet (HFD)-induced NAFLD. METHODS: NAFLD was induced in ApoE mice via a 12-week HFD regimen, with concurrent oral administration of low- (1.7 mg/kg) or high-dose (17 mg/kg) EGT. We integrated in vivo multi-omics profiling with in vitro assays to identify the metabolic pathways modulated by EGT. RESULTS: EGT administration robustly ameliorated HFD-induced hepatic steatosis, liver injury, and dyslipidemia. We identified a critical regulatory axis wherein EGT inhibits phosphatidylethanolamine cytidylyltransferase 2 (PCYT2) expression, thereby dampening the accumulation of pathogenic phosphatidylethanolamine (PE) species. This suppression of PE synthesis acts as a trigger to upregulate acyl-CoA thioesterase 8 (ACOT8), a key enzyme in lipid turnover. Notably, the protective effects of EGT against palmitic acid-induced lipid accumulation were blunted by the PE synthesis inhibitor meclizine, validating the PE-ACOT8 pathway as the primary target of EGT. CONCLUSION: This study unveils a previously unrecognized mechanism by which EGT alleviates NAFLD: the restoration of the PCYT2/PE/ACOT8 signaling axis. By correcting phospholipid composition to upregulate ACOT8, EGT restores lipid homeostasis, presenting a compelling natural compound-based strategy for NAFLD intervention.
Angelica dahurica alleviates peripheral nerve injury-induced muscle atrophy via the Phlpp2-Akt-FoxO3α axis independently of analgesia.
Wu D, Wang P, Liu X … +6 more , Li H, Zhong Y, Li W, Yang J, Xu H, Guo L
Phytomedicine · 2026 Aug · PMID 42275876 · Publisher ↗
BACKGROUND: Peripheral nerve injury frequently causes refractory neuropathic pain and muscle atrophy. While clinical care focuses on analgesia, effective therapies for muscle wasting are lacking. Angelica dahurica (BZ) i...
BACKGROUND: Peripheral nerve injury frequently causes refractory neuropathic pain and muscle atrophy. While clinical care focuses on analgesia, effective therapies for muscle wasting are lacking. Angelica dahurica (BZ) is known for its analgesic properties, but whether it also ameliorates muscle atrophy remains unclear. PURPOSE: This study evaluates the dual analgesic and anti‑atrophic effects of BZ, with a focus on determining whether its muscle‑protective action is separable from pain relief and elucidating the underlying mechanism. METHODS: Following sciatic nerve chronic constriction injury (CCI), rats were treated with BZ extract or Pregabalin (Pre), a positive analgesic control. Nociceptive behaviors and motor function were assessed via behavioral tests and gait analysis. Muscle atrophy was evaluated by wet weight, histology, and transmission electron microscopy. RNA‑seq was performed to profile transcriptomic changes in muscle. High‑resolution mass spectrometry was used to identify BZ‑derived components in plasma and muscle. RESULTS: Post-CCI muscle atrophy and pain showed distinct temporal trajectories, with atrophy transitioning from an acute phase of rapid mass loss (days 1-10) to a later phase of progressive fibrosis (days 14-21). BZ administration significantly alleviated mechanical, cold, and thermal hypersensitivity, while concurrently increasing muscle mass and partially improving myofiber morphology and sarcomere ultrastructure. Notably, while Pre provided equivalent analgesia, it failed to mitigate muscle atrophy, demonstrating that the anti-atrophic effect of BZ is largely independent of its analgesic activity. Mechanistically, BZ-mediated recovery was associated with the modulation of the intramuscular Phlpp2‑Akt‑ FoxO3α signaling axis, as indicated by suppressed Phlpp2 expression and enhanced Akt phosphorylation. Seven muscle-distributed components were identified as potential contributors to these therapeutic effects. CONCLUSIONS: BZ exerts potential anti-atrophic effects that correlated with modulation of the Phlpp2‑Akt‑FoxO3α axis, largely independent of its analgesic activity. These findings identify BZ as a promising dual-action therapeutic candidate for addressing both neuropathic pain and muscle wasting following peripheral nerve injury.
Bioactive compound emodin from clinical formula Zhi-Lou-Xun-Xi decoction exerts rapid analgesic effects by targeting TRPV1.
Chen C, Jin Z, Qiu Z … +12 more , Chen Z, Zhou JY, Hou W, Bu Z, Yao S, Ma Y, Yin H, Ma J, Cao X, Wang J, Zhang Y, Chen Y
Phytomedicine · 2026 Aug · PMID 42275875 · Publisher ↗
BACKGROUND: Effective postoperative pain management after hemorrhoidectomy remains a significant clinical challenge, largely due to the scarcity of safe and effective non-opioid analgesics. Zhi-Lou-Xun-Xi decoction (J5)...
BACKGROUND: Effective postoperative pain management after hemorrhoidectomy remains a significant clinical challenge, largely due to the scarcity of safe and effective non-opioid analgesics. Zhi-Lou-Xun-Xi decoction (J5) is a traditional Chinese formula that has been used clinically for decades, yet its active components and mechanism of action remain unclear. PURPOSE: This study aimed to systematically identify the active analgesic components in J5 and elucidate their molecular mechanism of action. METHODS: We employed an integrated pharmacological approach, beginning with a retrospective clinical analysis to confirm the analgesic and wound-healing effects of J5. Pharmacodynamic assays were conducted to evaluate its interaction with TRPV1. High-resolution mass spectrometry and structure-based virtual screening were used to identify candidate compounds. The mechanism of emodin, the primary active constituent, was further investigated through SPR assays, patch-clamp recording, molecular dynamics simulations, and extensive in vivo pain models using TRPV1 knockout (KO) mice. RESULTS: Emodin was identified as the key TRPV1-antagonizing component in J5. In multiple pain models, emodin produced dose-dependent analgesia without inducing common TRPV1 antagonist-related side effects, particularly altered thermal sensitivity or hyperthermia. These findings not only clarify the mechanistic basis of J5's clinical efficacy but also position emodin as a promising topical analgesic candidate that acts via local TRPV1 inhibition.
Shegan Mahuang Decoction ameliorates pulmonary fibrosis progression by inhibiting CCL3-mediated NETosis.
Zhou W, Wang Z, Du H … +5 more , Zhao W, Zhang T, Liu Z, Qu J, Sun Y
Phytomedicine · 2026 Aug · PMID 42275874 · Publisher ↗
BACKGROUND: Pulmonary fibrosis (PF) represents a spectrum of chronic lung disorders for which effective therapeutic options remain limited. Shegan Mahuang Decoction (SGMH) is a traditional Chinese medicine with potential...
BACKGROUND: Pulmonary fibrosis (PF) represents a spectrum of chronic lung disorders for which effective therapeutic options remain limited. Shegan Mahuang Decoction (SGMH) is a traditional Chinese medicine with potential therapeutic effects for respiratory system diseases. The precise mechanism of SGMH in treating PF has not yet been elucidated. PURPOSE: This study aims to investigate the effectiveness and mechanism of SGMH in the treatment of PF. METHODS: To investigate the effect of SGMH on PF, we established a mouse model and assessed inflammatory and neutrophil extracellular traps (NETs)-related markers. The target gene of SGMH was screened through integrated multi-omics analysis. The mechanisms of SGMH were explored through a series of experiments, encompassing NETs depletion with DNase I, the Pad4 mouse model, and pharmacological modulation via intraperitoneal administration of recombinant CCL3 (rCCL3) or a CCL3 neutralizing antibody (anti-CCL3). RESULTS: SGMH ameliorated Bleomycin-induced lung tissue damage. It also inhibited pulmonary inflammation and NETs formation. Both DNase I-mediated NETs clearance and the Pad4 mice model showed that SGMH could not further ameliorate PF, indicating that SGMH blocks the PF development by inhibiting NETs formation. Multi-omics analysis and experimental validation found that SGMH inhibits NETs formation by targeting CCL3. Administration of rCCL3 restored NETs formation and attenuated the anti-fibrotic effect of SGMH. Moreover, treatment with anti-CCL3 alone inhibited PF, whereas its combination with SGMH did not further enhance the therapeutic effect. CONCLUSION: This study demonstrated that SGMH ameliorates PF progression by inhibiting CCL3-mediated NETosis, suggesting its potential clinical application for PF treatment.
Network-guided identification and in vitro/in vivo validation of Withaferin A as an inhibitor of nuclear factor kappa B for spinal cord injury repair.
Xie C, Zhang C, Zhang Y … +6 more , Chen L, He X, Xie X, Li K, Wang X, Lv C
Phytomedicine · 2026 Aug · PMID 42275873 · Publisher ↗
BACKGROUND: Spinal cord regeneration after injury remains a major clinical challenge due to the persistent inflammatory microenvironment associated with immune cell infiltration. Withaferin A (WA), a natural anti-inflamm...
BACKGROUND: Spinal cord regeneration after injury remains a major clinical challenge due to the persistent inflammatory microenvironment associated with immune cell infiltration. Withaferin A (WA), a natural anti-inflammatory steroidal lactone with potential NF-κB-modulating activity, was identified by network-based screening as a candidate for spinal cord injury (SCI) and selected for further study. PURPOSE: This study aimed to identify and evaluate potential anti-inflammatory small-molecule therapeutics for SCI using a network-based drug screening strategy. STUDY DESIGN: Experimental study combining computational drug screening, in vitro macrophage assays and in vivo SCI mouse models. METHODS: Network pharmacology identified 296 candidate drugs targeting 113 SCI-related genes. Five top candidates, selected for chemical diversity and accessibility, were tested in LPS-stimulated in vitro models for effects on macrophage polarization and cytokine release. Molecular docking was used to predict drug-target interactions. The lead compound, WA, was then evaluated in SCI mice for inflammation, angiogenesis, neuroregeneration and motor recovery. RESULTS: WA showed the strongest anti-inflammatory activity, dose-dependently inhibiting LPS-induced M1 polarization and TNF-α/IL-6 secretion while promoting M2 polarization and IL-4/IL-10 secretion. Integrated computational and experimental analyses identified Cys160 in a hydrophobic pocket of NF-κB p65 as the covalent binding site of WA. In vivo, WA modulated macrophage polarization, reduced inflammatory mediator secretion, increased VEGF immunoreactivity and promoted neuroregeneration and motor recovery. CONCLUSION: WA exerts significant anti-inflammatory and neuroregenerative effects in SCI models. It also increases VEGF immunoreactivity, suggesting a potential pro-angiogenic effect after injury. These findings support WA as a promising therapeutic candidate for SCI.
Discovery of self-assembled nanoparticles from Rubia cordifolia L. before and after carbonization and mechanistic study on their targeted therapy for ulcerative colitis.
Li K, Ren R, Qi Y … +5 more , Wang M, Zhang Q, Sun J, Wang J, Zhao C
Phytomedicine · 2026 Aug · PMID 42269185 · Publisher ↗
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited treatment options. The carbonization of Rubia cordifolia L. traditionally enhances its therapeutic effects, but the mechanism remai...
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited treatment options. The carbonization of Rubia cordifolia L. traditionally enhances its therapeutic effects, but the mechanism remains unclear. OBJECTIVE: To investigate whether carbonization induces self‑assembled nanoparticles (PRCL NPs) from Rubia cordifolia and to elucidate their mechanism in UC. STUDY DESIGN: Self‑assembled nanoparticles were extracted from raw (RCL NPs) and carbonized (PRCL NPs) Rubia cordifolia. A DSS‑induced acute UC mouse model was used to evaluate efficacy. Transcriptomics, proteomics, Western blot, and ELISA were performed to explore the mechanism. METHODS: Nanoparticles were characterized by DLS, SEM, FTIR, and stability assays. DSS‑induced colitis mice were orally treated with RCL NPs or PRCL NPs (1.3 and 5.2 g/kg). Inflammatory and pathway markers were assessed. RESULTS: PRCL NPs exhibited smaller particle size (337.2 nm vs. 947.2 nm) and enhanced stability (zeta potential -15.2 mV). Multi‑omics revealed convergent enrichment of the IL‑17 signaling pathway. PRCL NPs significantly upregulated IL‑17A, IL‑22, p‑STAT3, and p‑C/EBPβ (p < 0.001) and suppressed chemokines CCL5, CXCL5, and CXCL10. CONCLUSION: Carbonization of Rubia cordifolia spontaneously forms structurally optimized self‑assembled nanoparticles (PRCL NPs) that alleviate UC by modulating the IL‑17A/IL‑22-C/EBPβ-STAT3 axis. This study provides a modern nanoscale interpretation of traditional processing theory.
Farrerol alleviates obesity and hepatic steatosis by targeting translational regulation to coordinate cellular stress and lipid metabolism.
Huang S, Wang J, Ma S … +6 more , Li L, Sun S, Zhou Y, Qian C, Zhang M, Liu Y
Phytomedicine · 2026 Aug · PMID 42269184 · Publisher ↗
BACKGROUND: Dysregulation of lipid metabolism is a primary driver of obesity and related metabolic disease. Farrerol is a dihydroflavonoid derived from Rhododendron dauricum L., has known anti-inflammatory and antioxidan...
BACKGROUND: Dysregulation of lipid metabolism is a primary driver of obesity and related metabolic disease. Farrerol is a dihydroflavonoid derived from Rhododendron dauricum L., has known anti-inflammatory and antioxidant properties, but its potential role in regulating lipid metabolism and the underlying mechanisms remains unclear. PURPOSE: This study aimed to investigate the effect of farrerol on lipid metabolism and explore its potential molecular mechanisms using multi-model systems. METHODS: The lipid-lowering efficacy of farrerol was initially evaluated in Caenorhabditis elegans (C. elegans) under physiological and citrate-induced high-fat conditions. RNA-seq and RNA interference (RNAi) screening were utilized to identify genes involved in the lipid-regulating effect of farrerol. The lipid-lowering effects and mechanisms were further validated in vitro and in vivo using biochemical assays, untargeted lipidomics, and target-identification approaches including DARTS and CETSA. RESULTS: In C. elegans, farrerol treatment reduces lipid accumulation induced by citric acid and promoted DAF-16 nucelar translocation. RNA-seq and RNAi screening identified F44E5.4/F44E5.5 and uev-2 as essential upstream regulators for lipid lower effect and DAF-16 activation. In vitro and in vivo, farrerol effectively suppressed hepatic steatosis, modulated hepatic lipid profiles by reducing highly lipotoxic triglycerides, and ameliorated hyperinsulinemia in DIO mice. Mechanistically, target screening revealed that farrerol directly binds to eukaryotic translation initiation factor 4 gamma 1 (eIF4G1). This interaction rescues the expression of the chaperone HSP72, the mammalian ortholog of F44E5.4/5.5, which in turn stabilizes AMPK, thereby inhibiting SREBP1-mediated de novo lipogenesis. CONCLUSION: Farrerol alleviates lipid accumulation through a conserved eIF4G1/HSP72/AMPK signaling across species. These findings highlight the direct molecular target of farrerol and support its potential as a promising natural therapeutic agent for obesity and hepatic steatosis.
Entagenic acid targets ASCC2 to ameliorate allergic contact dermatitis via repressing NF‑κB transactivation and chemokine expression.
Xiong H, Yu J, Zhang N … +7 more , Li R, Yan T, Wang X, Zheng J, Zhang W, Yang J, Mei Z
Phytomedicine · 2026 Aug · PMID 42269183 · Publisher ↗
BACKGROUND: Allergic contact dermatitis (ACD) is an inflammatory skin disease triggered by allergen exposure. Entagenic acid (EA) is the main triterpene aglycone isolated from Entada phaseoloides, which has been document...
BACKGROUND: Allergic contact dermatitis (ACD) is an inflammatory skin disease triggered by allergen exposure. Entagenic acid (EA) is the main triterpene aglycone isolated from Entada phaseoloides, which has been documented to treat dermatitis, exhibits anti-inflammatory properties. However, its molecular mechanism in ACD remains unexplored. PURPOSE: This study aimed to investigate the therapeutic effect of EA against ACD and explore its underlying molecular target and mechanism. METHODS: The therapeutic effect of EA on ACD was evaluated in TNF-α/IFN-γ-stimulated keratinocytes and Squaric acid dibutylester (SADBE)-induced ACD mouse models. Integrated approaches including DrugBAN, GraphDTA, and thermal proteome profiling identified Activating Signal Cointegrator 1 Complex Subunit 2 (ASCC2) as the direct target of EA, which was confirmed by CETSA and ITC. The mechanism of EA targeting ASCC2 to alleviate keratinocytes inflammation was elucidated through transcriptomics, co-immunoprecipitation, and RNA interference. In vivo, intradermal injection of rAAV.DJ-CMV-ASCC2 was used to verify the ASCC2-dependent therapeutic effect of EA in ACD mice. RESULTS: Our study revealed that EA suppressed the expression of CXCL10 and CCL2 in keratinocytes and alleviated ACD-like symptoms in mice. EA decreased the mRNA levels of chemokines and regulated the NF-κB pathway through interrupting the interaction between ASCC2 and p65 in keratinocytes. In vivo, we also demonstrated that the overexpression of ASCC2 on skin of ACD mice reduced the EA-induced therapeutic effect. CONCLUSION: Our findings demonstrate that EA directly binds to ASCC2, attenuates NF-κB pathway transactivation, reduces key chemokine expression, and suppresses ACD-like progression, highlighting its potential as a therapeutic candidate for ACD.
Rhein antagonizes glucocorticoid receptor signaling to activate SIRT1-dependent thermogenesis in brown adipose tissue and ameliorate obesity.
Gu P, Zhao X, Mao L … +12 more , Song P, Guo Q, Wang W, Lv L, Xue M, Pik-Shan Kong A, Sun W, Zhang Y, Wu D, Lu B, Hui HX, Shao J
Phytomedicine · 2026 Aug · PMID 42269182 · Publisher ↗
BACKGROUND: The obesity pandemic necessitates therapies that safely increase energy expenditure. Brown adipose tissue (BAT) is a key organ for energy dissipation. While the natural compound rhein has anti-obesity effects...
BACKGROUND: The obesity pandemic necessitates therapies that safely increase energy expenditure. Brown adipose tissue (BAT) is a key organ for energy dissipation. While the natural compound rhein has anti-obesity effects, its action on BAT and the mechanism remain unclear. PURPOSE: This study examined the effects of rhein on BAT activation and its underlying mechanism. STUDY DESIGN AND METHODS: Diet-induced obese wildtype (WT) and adipocyte-specific Sirt1 knockout (AKO) mice were treated with rhein. Metabolic phenotyping including energy expenditure was measured. Brown adipocytes were differentiated in vitro and treated with rhein. Biotin-labeled rhein pull-down and glucocorticoid receptor (GR) activity assays were conducted to identify the molecular target of rhein and assess its effect on GR activity. RESULTS: Rhein treatment robustly protected mice from high-fat diet-induced obesity, improved glucose homeostasis, and increased whole-body energy expenditure. These benefits were accompanied by BAT activation, as evidenced by elevated body temperature, upregulation of UCP1, and enhanced mitochondrial biogenesis. Mechanistically, rhein directly bound to the ARGLU1, a co-activator of GR, thereby antagonizing GR signaling. This inhibition relieved GR-mediated suppression of JNK, leading to JNK-dependent phosphorylation and stabilization of SIRT1. Critically, the anti-obesity and thermogenic effects of rhein were significantly abolished in AKO mice. Furthermore, rhein effectively counteracted corticosterone-induced obesity, BAT whitening, and SIRT1 downregulation. CONCLUSION: Our findings identify rhein as a potent BAT activator that ameliorates obesity through a novel ARGLU1-GR-JNK-SIRT1 axis. This work not only unravels the molecular mechanism of rhein-elicited metabolic benefits in BAT, but also positions it as a promising therapeutic candidate for both overnutrition- and glucocorticoid-related metabolic disorders.
Paclitaxel and triptolide impair MYC-driven cell cycle via suppressing chromatin reprogramming in ALDH1A3 pancreatic cancer.
Nie S, Jiang Y, Meng L … +10 more , Dai Z, Wu Y, Wang K, Li H, Yu Y, Shi Z, Friess H, Wang L, Kong B, Shen S
Phytomedicine · 2026 Aug · PMID 42269181 · Publisher ↗
BACKGROUND AND PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by transcriptional heterogeneity and chemoresistance. We previously identified an aggressive PDAC subtype define...
BACKGROUND AND PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterized by transcriptional heterogeneity and chemoresistance. We previously identified an aggressive PDAC subtype defined by high expression of aldehyde dehydrogenase 1 family member A3 (ALDH1A3), which sustained a basal-like transcriptional program through AP-1-dependent enhancer remodeling. However, effective therapeutic strategies for ALDH1A3 PDAC remain undefined. This study aimed to identify subtype-specific therapeutic vulnerabilities, and define their chromatin-based mechanisms. METHODS: Public datasets, patient-derived cell cultures, and in vivo xenograft models were utilized to evaluate targeted drug effects, while associated chromatin regulatory mechanisms were interrogated using an integrative multi-omics framework combining RNA-seq, ATAC-seq, and functional assays. RESULTS: Based on drug screening system, paclitaxel and triptolide effectively suppressed the ALDH1A3-associated transcriptional network, producing robust antitumor activity and significantly prolonging survival in ALDH1A3 models. Further integrated RNA-seq and ATAC-seq analyses revealed that paclitaxel and triptolide converge on AP-1-dependent enhancer regulation, inducing widespread chromatin closure at distal regulatory elements and leading to the coordinated downregulation of MYC and its dimerization partner MAX. Functionally, MYC inhibition mimicked the effects of paclitaxel and triptolide, reproducing the suppression of E2F3 and subsequent cell-cycle arrest. CONCLUSION: The paclitaxel-triptolide combination represented a rational therapeutic strategy that disrupted lineage-specific chromatin states and might offer a clinically relevant approach for improving outcomes in ALDH1A3 PDAC patients.
Licochalcone B alleviates pulmonary vascular remodeling via inhibiting Furin/TGF-β1 in pulmonary hypertension.
Gong D, Liu R, Deng X … +5 more , Xing J, Zhang X, Du G, Yuan T, Fang L
Phytomedicine · 2026 Aug · PMID 42263545 · Publisher ↗
BACKGROUND: Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, and Furin, a proprotein convertase critical for TGF-β1 activation, has shown promise as a novel therapeutic target for PH. Howeve...
BACKGROUND: Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, and Furin, a proprotein convertase critical for TGF-β1 activation, has shown promise as a novel therapeutic target for PH. However, its specific role in PH pathogenesis and potential inhibitors have remained unexplored. PURPOSE: This study aimed to investigate the role of Furin in PH-associated vascular remodeling and evaluate the therapeutic potential of the newly discovered Furin inhibitor, Licochalcone B (LicoB), in PH. METHODS: We assessed Furin expression levels in multiple PH animal models and evaluated its cellular localization using single-cell transcriptomics. Then the functional role of Furin was validated through overexpression and knockdown studies in vitro. The protective effect of Furin inhibitor, LicoB, was validated in pulmonary artery vascular cells, and finally its therapeutic effects and potential mechanisms were evaluated in PH animal models. RESULTS: Elevated Furin expression was consistently observed across diverse PH animal models. Furin overexpression promoted cell viability and migration, while its knockdown mitigated pathological features. The Furin inhibitor, LicoB, effectively suppressed aberrant pulmonary artery cell proliferation and migration, and restored mitochondrial membrane potential in vitro. Critically, in both murine and rat PH models, LicoB administration significantly ameliorated symptoms, exerted robust cardiopulmonary protection, and attenuated pulmonary vascular remodeling. Mechanistically, LicoB acted by inhibiting the Furin/TGF-β1 signaling axis. CONCLUSION: Our findings establish Furin as a key driver of PH development and demonstrate that LicoB suppresses vascular remodeling via the Furin/TGF-β1 pathway, positioning LicoB as a highly promising novel therapeutic candidate for PH by targeting Furin.
Dihydrotanshinone I inhibits PHGDH to suppress serine synthesis and remodel TME in NSCLC.
Qian C, Han H, Wan L … +9 more , Huang Y, Luo Y, Wang Z, Cheng P, Gao M, Fan W, Lu Y, Zhao Y, Wang L
Phytomedicine · 2026 Aug · PMID 42263544 · Publisher ↗
BACKGROUND: The strategy of limiting the availability of tumor cell phosphoglycerate dehydrogenase (PHGDH) has become a potential treatment for cancer. Modulation of the tumor-derived serine synthesis pathway to reprogra...
BACKGROUND: The strategy of limiting the availability of tumor cell phosphoglycerate dehydrogenase (PHGDH) has become a potential treatment for cancer. Modulation of the tumor-derived serine synthesis pathway to reprogram the tumor microenvironment represents a viable approach to optimize the efficacy of anti-tumor immunotherapy. However, currently no reliable PHGDH inhibitors of natural product origin have been approved for clinical use, and the precise pharmacological mechanisms underlying their biological activity have not yet been fully elucidated. PURPOSE: This study aims to identify PHGDH inhibitors from natural products and elucidate the underlying anti-tumor pharmacological mechanisms. METHODS: Multiple public databases were utilized to analyze the correlation between PHGDH and human non-small cell lung cancer (NSCLC) in this study. We took advantage of a natural compound library to perform the compound screening of PHGDH inhibitors. The binding capacity of DHT I to PHGDH was examined using molecular docking simulations, cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and microscale thermophoresis (MST). Co-immunoprecipitation and western blotting assays were employed to investigate the regulatory effect of DHT I on PRMT1-mediated monomethylation of PHGDH. The roles of DHT I in PHGDH-mediated serine synthesis pathway in the lung cancer cells were determined through metabolomics analysis. Western blotting analysis was performed to examine the regulatory impact of DHT I on histone H3 lysine 4 methylation (H3K4me). Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were utilized to determine the effects of DHT I on the transcriptional and secretory levels of IL-10 and TGF-β. Co-culture assays of tumor cells and bone marrow-derived macrophages (BMDMs) were performed to investigate DHT I-mediated polarization of macrophages. Single-cell RNA sequencing (scRNA-seq) analysis was performed to elucidate the molecular mechanisms underlying DHT I-mediated suppression of lung cancer progression in a murine model. Combined administration of DHT I and anti-PD-1 was employed to evaluate the therapeutic efficacy of this combinatorial regimen for anti-tumor immunotherapy. RESULTS: Elevated PHGDH expression and enzymatic activity were closely correlated with poor clinical prognosis in patients with NSCLC. DHT I was identified as a novel PHGDH inhibitor with therapeutic potential for NSCLC. DHT I bound to PHGDH at the Arg236 residue, which abrogated PRMT1-mediated methylation of PHGDH and consequently induced its functional inactivation. It also demonstrated that DHT I-mediated PHGDH inhibition reprograms the serine synthesis pathway in lung cancer cells, thereby reducing intracellular L‑serine and S-Adenosylmethionine (SAM) levels. DHT I downregulates H3K4me expression and suppresses the transcription of IL-10 and TGF-β, thereby modulating macrophage polarization in the tumor microenvironment. Furthermore, scRNA-seq analysis revealed that DHT-I-mediated reprogramming of tumor metabolism and alterations of the macrophage signature reversed the tumor immunosuppressive microenvironment, thereby potentiating the efficacy of anti-PD-1-based immunotherapy. CONCLUSION: Collectively, our findings demonstrate that DHT I is a potent PHGDH inhibitor with the potential for further optimization as a candidate agent for combination with immunotherapy to suppress the progression of NSCLC.
Cucurbitacin B targets PPAT to suppress de novo purine biosynthesis in esophageal squamous cell carcinoma.
Jia H, Guo J, Luo H … +8 more , Zhou X, Hou D, Khan A, Xue Y, Dai Z, Qiao Y, Song M, Dong Z
Phytomedicine · 2026 Aug · PMID 42259163 · Publisher ↗
BACKGROUND: The de novo purine biosynthesis (DNPB) pathway is increasingly recognized as a key driver of tumor progression. Nevertheless, its precise role in regulating esophageal squamous cell carcinoma (ESCC) growth, r...
BACKGROUND: The de novo purine biosynthesis (DNPB) pathway is increasingly recognized as a key driver of tumor progression. Nevertheless, its precise role in regulating esophageal squamous cell carcinoma (ESCC) growth, radiosensitivity, and therapeutic response has not been fully elucidated. PURPOSE: This study aimed to determine contribution of phosphoribosyl pyrophosphate amidotransferase (PPAT), the rate-limiting enzyme of the DNPB pathway, in ESCC progression and potential therapeutic benefit of PPAT-targeted intervention. METHODS: Single-cell RNA sequencing and untargeted metabolomics analyses were used to characterize PPAT-associated metabolic changes in ESCC. Structure-based virtual screening was performed to identify potential PPAT inhibitors. The interaction and degradation of PPAT by Cucurbitacin B (CuB) were investigated using docking, pull-down, CETSA, and ubiquitination assays, and its anti-tumor and radiosensitizing effects were evaluated in vitro and in vivo. RESULTS: We identified PPAT as a critical modulator of ESCC malignancy. PPAT promoted the production of energy-related nucleotides, including AMP, GMP, ADP, GDP, ATP, and GTP, thereby fueling ESCC tumor growth in vitro and in vivo. Moreover, CuB specifically targeted PPAT and induced its polyubiquitin-mediated degradation via TRIM38, thereby suppressing the DNPB pathway and inhibiting tumor growth. Importantly, CuB also functioned as a radiosensitizer, significantly enhancing the therapeutic efficacy of radiotherapy in ESCC. CONCLUSION: In conclusion, our findings reveal that targeting PPAT is a promising therapeutic strategy to suppress ESCC progression and enhance the efficacy of radiotherapy.
Rehmannioside D prevents estrogen-deficiency induced osteoporosis by interacting with c-Jun to dismantle the AP-1 complex and suppress MAPK/NF-κB signaling.
Wang Y, Wu J, Liu H … +6 more , Zhang Y, Sheng X, Li X, Gao H, Lu Q, Ji Y
Phytomedicine · 2026 Aug · PMID 42251792 · Publisher ↗
BACKGROUND: Postmenopausal osteoporosis (PMOP) necessitates novel therapeutics with defined targets. Rehmannioside D (RD), a bioactive compound from Rehmannia glutinosa, exhibits anti-inflammatory properties, yet its ant...
BACKGROUND: Postmenopausal osteoporosis (PMOP) necessitates novel therapeutics with defined targets. Rehmannioside D (RD), a bioactive compound from Rehmannia glutinosa, exhibits anti-inflammatory properties, yet its anti-osteoporotic mechanism remains unclear. PURPOSE: This study integrated network pharmacology with experimental validation to elucidate the efficacy and mechanism of RD in suppressing osteoclastogenesis. METHODS: Potential targets were screened via network pharmacology. In vitro, the effects of RD on RANKL-induced osteoclast differentiation and function were assessed in bone marrow-derived macrophages (BMDMs). Target interaction was verified using Cellular Thermal Shift Assay (CETSA), molecular docking, and Co-IP. In vivo, osteoprotective efficacy was evaluated in ovariectomized (OVX) mice. RESULTS: Network analysis highlighted c-Jun and c-Fos as core targets. In vitro, RD significantly inhibited osteoclastogenesis and resorptive function without cytotoxicity. Mechanistically, RD exerted a dual inhibitory effect: It suppressed the activation of MAPK and NF-κB signaling pathways, thereby downregulating NFATc1 expression and inhibiting osteoclast differentiation; Distinctly, RD was identified to interact with and stabilize to c-Jun, sterically hindering its heterodimerization with c-Fos to dismantle the AP-1 complex. This disruption of AP-1 subsequently triggered intrinsic apoptosis, evidenced by an elevated Bax/Bcl-2 ratio and Caspase-3 cleavage. In vivo, RD prevented trabecular bone loss and preserved microarchitecture in OVX mice by reducing osteoclast numbers. CONCLUSION: RD attenuates bone loss via a dual mechanism: it inhibits osteoclast differentiation by suppressing MAPK/NF-κB signaling and simultaneously induces mature osteoclast apoptosis by targeting c-Jun to disrupt the AP-1 complex.
Huanglian Wendan ameliorates depression via gut-brain axis-related PPAR-α/allo pathways.
Sun Q, Zhao Y, Zhang J … +7 more , Shuang R, Li W, Huang W, Chen C, Zhao F, Cheng X, Tao W
Phytomedicine · 2026 Aug · PMID 42250464 · Publisher ↗
BACKGROUND: Huanglian Wendan decoction (HLWD) is traditionally used to treat a syndrome characterized by symptoms such as insomnia, irritability, and digestive disturbances. Its historical application in addressing phleg...
BACKGROUND: Huanglian Wendan decoction (HLWD) is traditionally used to treat a syndrome characterized by symptoms such as insomnia, irritability, and digestive disturbances. Its historical application in addressing phlegm-heat-induced mental and emotional disorders offers both a cultural and clinical basis for investigating its potential mechanisms in alleviating depressive symptoms via gut-brain axis. PURPOSE: To explore the potential therapeutic mechanisms of HLWD in improving depression. METHODS: Behavioral outcomes were assessed using the SPT, TST, OFT, and SIT. Neurogenesis was evaluated by measuring dendritic length and neuronal intersections. Allopregnanolone levels were measured using ELISA. Inflammatory signaling pathways (TLR4, MyD88, NF-κB) and cytokines (IL-1β, TNF-α, IL-10, IL-4) in the hippocampus were analyzed via WB. The integrity of the intestinal barrier was further validated through immunofluorescence and histological examination. Finally, GW6471 was employed to investigate whether PPAR-α mediates the effects of HLWD. RESULTS: The UPLC analysis identified 42 constituents, primarily comprising flavonoids, alkaloids, and coumarins. Behavioral assays demonstrated that HLWD effectively ameliorated depressive-like behaviors in mice. Mechanistically, HLWD elevated the levels of DCX-positive neurogenesis markers, inhibited microglial activation, protected the intestinal mucosal barrier, and reduced inflammatory responses in both the colon and hippocampus. The RNA-seq results indicated an enrichment of the PPAR signaling pathway in colon. Consistent with this finding, HLWD significantly upregulated both the protein and mRNA levels of PPAR-α in the colon. Meanwhile, it increased the concentration of allopregnanolone in hippocampal via peripheral circulation. Notably, the administration of the PPAR-α antagonist GW6471 reversed these neuroprotective effects and the associated protein changes, thereby underscoring the critical role of PPAR-α in the therapeutic mechanism of HLWD. CONCLUSION: HLWD can elevate the levels of PPAR-α and allopregnanolone in the colon, subsequently influencing the levels of allopregnanolone in the hippocampus via peripheral circulation. This process may enhance neurological function and alleviate depressive symptoms.
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