Multi-target Mechanism Research Articles

Excessive fructose consumption is strongly linked to metabolic syndrome, with gut microbiota playing a pivotal role in mediating fructose metabolism and associated metabolic disturbances. In this study, we aimed to characterize Apilactobacillus (A.) kunkeei, a fructophilic lactic acid bacterium from honey, and evaluate its probiotic function in male C57BL/6 J mice fed a high-fructose diet (HFD). Transcriptome analysis was carried out to analyze the activation of pathways under various culture conditions. Pathway inhibitors were used in cell culture and a hepatectomy mouse model to study the function of different pathways in hepatocyte growth and liver regeneration. Our results showed that A. kunkeei FM01 exhibited strong tolerance to simulated gastrointestinal stress in vitro, indicating good probiotic potential. Administration of A. kunkeei FM01 significantly reduced body weight gain, improved glucose tolerance, and attenuated hepatic and visceral (perirenal and epididymal) lipid accumulation in HFD-fed mice. Serum lipid profiling and targeted lipidomic analysis revealed that A. kunkeei FM01 lowered triglycerides, phosphatidylcholine, and lysophosphatidylcholine levels while increasing beneficial phospholipids such as phosphatidylethanolamine. Metagenomic analysis demonstrated that A. kunkeei FM01 modulated gut microbiota composition by reducing pro-inflammatory and fructose-metabolizing taxa, including Alistipes, Oscillibacter, Desulfovibrio, Lawsonibacter, and Enterococcus, while enriching beneficial species, including Kineothrix alysoides and Faecalibaculum rodentium. These microbial shifts were associated with increased abundances in genes encoding carbohydrate-active enzymes and amino acid biosynthesis pathways. Furthermore, A. kunkeei FM01 restored intestinal barrier integrity by upregulating tight junction proteins (Zonula Occludens-1 and occludin) and reduced serum lipopolysaccharide and diamine oxidase levels. Collectively, these findings suggest that A. kunkeei FM01 exerts protective effects against HFD-induced metabolic dysfunction through multi-targeted mechanisms involving lipid metabolism, gut microbiota modulation, and intestinal barrier restoration. This study identifies A. kunkeei FM01 as a promising probiotic candidate for preventing and managing fructose-associated metabolic disorders.

Acute respiratory distress syndrome (ARDS) is a severe and life-threatening complication of COVID-19, for which no specific antiviral treatment currently exists. Shenfu Injection (SFI), a traditional Chinese medicine formulation, has shown clinical promise in improving respiratory function and reducing mortality in ARDS patients. However, its underlying molecular mechanisms remain poorly understood. A combined network pharmacology and bioinformatics approach was used to elucidate the potential mechanisms of SFI against COVID-19-induced ARDS. SFI-related targets were identified through multiple public databases, followed by Gene Ontology (GO) and KEGG pathway enrichment analyses. Gene expression data from GEO datasets (GSE171110 and GSE273149) were used to identify differentially expressed genes in COVID-19-induced ARDS, which were then intersected with SFI targets. Molecular docking was performed to evaluate the binding affinities between major active compounds in SFI and core viral proteins, including 3CLpro, RdRp, and ACE2. A total of 398 SFI-associated targets were identified, with key targets including SRC, MAPK1, MAPK3, PIK3R1, and STAT3. Active compounds such as Gomisin B, Deoxyharringtonine, Ginsenoside-Rh4_qt, Suchilactone, and Celabenzine were highlighted. Enrichment analyses identified 2,883 GO terms and 219 KEGG pathways (P < 0.05), primarily involving the PI3K-Akt, MAPK, TNF, NF-κB, and apoptosis signaling pathways. GEO data analysis confirmed the involvement of these pathways in COVID-19-induced ARDS. Molecular docking showed strong binding affinities, particularly between Ginsenoside-Rh4_qt and 3CLpro/ACE2, and Celabenzine with RdRp. The findings suggest that SFI exerts therapeutic effects through modulation of key inflammatory and immune pathways and by direct interaction with SARS-CoV-2 viral proteins. This multi-target mechanism aligns with the pharmacological characteristics of traditional Chinese medicine. However, further experimental validation is required to confirm these computational predictions and assess clinical relevance. This study provides mechanistic insights into how SFI may alleviate COVID-19-induced ARDS via modulation of critical signaling pathways and interaction with viral targets, offering a theoretical foundation for its clinical application in the management of severe COVID-19 cases.

Background/Objectives: Cancer progression is characterized by the suppression of apoptosis, activation of metastatic processes, and dysregulation of cell proliferation. The proper functioning of these mechanisms relies on critical signaling pathways, including Phosphoinositide 3-kinase/Protein kinase B/mammalian Target of Rapamycin (PI3K/Akt/mTOR), Mitogen-Activated Protein Kinase (MAPK), and Signal Transducer and Activator of Transcription 3 (STAT3). Although curcumin and resveratrol exhibit anticancer properties and affect these pathways, their pharmacokinetic limitations, including poor bioavailability and low solubility, restrict their clinical application. The aim of our study was to evaluate the synergistic anticancer potential of curcumin and resveratrol through hybrid molecules rationally designed from these compounds to mitigate their pharmacokinetic limitations. Furthermore, we analyzed the multi-target anticancer effects of these hybrids on the AKT serine/threonine kinase 1 (AKT1), MAPK, and STAT3 pathways using in silico molecular modeling approaches. Methods: Three hybrid molecules, including a long-chain (ELRC-LC) and a short-chain (ELRC-SC) hybrid, an ester-linked hybrid, and an ether-linked hybrid (EtLRC), were designed using the Avogadro software (v1.2.0), and their geometry optimization was carried out using Density Functional Theory (DFT). The electronic properties of the structures were characterized through Frontier Molecular Orbital (FMO), Molecular Electrostatic Potential (MEP), and Fourier Transform Infrared (FTIR) analyses. The binding energies of the hybrid molecules, curcumin, resveratrol, their analogs, and the reference inhibitor were calculated against the AKT1, MAPK, and STAT3 receptors using molecular docking. The stabilities of the best-fitting complexes were evaluated through 100 ns molecular dynamics (MD) simulations, and their binding free energies were estimated using the Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) method. Results: DFT analyses demonstrated stable electronic characteristics for the hybrids. Molecular docking analyses revealed that the hybrids exhibited stronger binding compared to curcumin and resveratrol. The binding energy of −11.4 kcal/mol obtained for the ELRC-LC hybrid against AKT1 was particularly remarkable. Analysis of 100 ns MD simulations confirmed the conformational stability of the hybrids. Conclusions: Hybrid molecules have been shown to exert multi-target mechanisms of action on the AKT1, MAPK, and STAT3 pathways, and to represent potential anticancer candidates capable of overcoming pharmacokinetic limitations. Our in silico-based study provides data that will guide future in vitro and in vivo studies. These rationally designed hybrid molecules, owing to their receptor affinity, may serve as de novo hybrid inhibitors.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death and disability worldwide. Its complex etiology involves factors such as smoking, air pollution, genetic susceptibility, and social environment. With the accelerating global aging population and urbanization, the incidence and burden of COPD continue to rise. Current treatment strategies for COPD are relatively conservative, primarily focusing on bronchodilators, inhaled corticosteroids, and long-term oxygen therapy. Although these approaches can alleviate symptoms and slow disease progression to some extent, they fail to effectively target the underlying mechanisms of the disease, leaving an unmet clinical need for more-effective therapies. This highlights the urgency of developing innovative drugs that are both safe and efficacious to address the challenges in COPD treatment. As a traditional Chinese medicine with a long history, Colla corii asini has garnered significant attention for its diverse pharmacological effects and favorable safety profile. Research has shown that Colla corii asini possesses multiple biological activities, including hematopoiesis, nourishing the lungs, enhancing immunity, anti-infection, antiaging, antitumor, and antifatigue effects. Moreover, it has demonstrated potential in regulating oxidative stress, immune imbalance, and inflammatory responses. Recent evidence suggests that Colla corii asini may play a protective role in lung function through multitarget and multipathway mechanisms. Based on previous research findings, this paper explores the potential therapeutic value of Colla corii asini in COPD treatment by addressing the current clinical management challenges and identifying potential therapeutic targets. It also integrates the pharmacological effects of Colla corii asini into a broader treatment context, providing new perspectives for comprehensive COPD management and laying the theoretical foundation for its modernization and innovative application.

Cichorium intybus, commonly known as chicory, is acknowledged as a substitute for coffee and is widely utilized in medicinal applications to treat various ailments. Chicory extract is commonly used in the management of diabetes; however, the specific bioactive components remain unidentified. The present study displayed the antidiabetic potential of chicory using a comprehensive approach integrating in vitro, network pharmacology, and in silico techniques. The methanolic extract demonstrated significant α-glucosidase inhibitory activity in the initial experiment, indicating potential for the management of postprandial hyperglycemia. Based on this, chicory's major metabolites were identified and examined for their interactions with (type 2 diabetes) T2D targets using network pharmacology. The core genes and pathways involved in the disease were mapped to understand the multitarget mechanisms of the extract. A molecular docking study validated the binding affinity and interactions of leading bioactive compounds with T2D protein targets. The findings indicate that chicory metabolites may serve as promising candidates for the development of natural antidiabetic agents.

Cisplatin-induced acute kidney injury (AKI) represents a severe complication of anticancer therapy with no effective clinical interventions, frequently necessitating chemotherapy dose reduction or discontinuation. Natural products have emerged as promising therapeutic candidates against cisplatin nephrotoxicity due to their multi-target mechanisms, pleiotropic effects, and low resistance potential. This study explored the therapeutic potential of hesperetin (Hes) in ameliorating mitochondrial dysfunction during AKI through coordinated induction of autophagy and suppression of the cGAS-STING pathway. We established an HK-2 cell injury model through cisplatin exposure. Following Hes intervention, cell viability was quantified via CCK-8 assays, apoptosis assessed by Annexin V-FITC/PI staining, and mitochondrial function evaluated through ATP production measurement, mitochondrial reactive oxygen species (ROS) detection and mitochondrial membrane potential analysis employing JC-1 staining. For in vivo validation, C57BL/6 mice developed AKI following single intraperitoneal cisplatin administration. Renal function parameters were determined through serum biochemistry, while renal histopathology was examined using periodic acid-Schiff (PAS) staining. Protein expression changes in mitochondrial autophagy markers and cGAS-STING pathway components were subsequently analyzed through immunofluorescence and Western blotting techniques. Autophagy modulators were employed to elucidate the precise mechanisms through which autophagy mediates Hes's protective effects against cisplatin-induced AKI. In vitro, Hes intervention effectively reversed cisplatin-induced HK-2 cell injury and mitochondrial dysfunction while enhancing mitochondrial autophagy. Notably, the autophagy activator rapamycin alone, or co-administered with Hes produced comparable cytoprotective effects to Hes. Conversely, the autophagy inhibitor 3-methyladenine exacerbated cellular damage and partially attenuated Hes-mediated protection. In vivo studies confirmed Hes significantly ameliorated AKI through improved renal function and histopathology, concurrently reducing mitochondrial ROS levels while promoting autophagic clearance. Furthermore, Hes treatment potently suppressed activation of the cGAS-STING pathway in both experimental models. Hes ameliorates mitochondrial dysfunction in AKI by enhancing mitochondrial autophagy and inhibiting the cGAS-STING pathway.

Iris tectorum Maxim. (CSG) is a notable traditional Chinese medicinal herb recognized for its broad pharmacological activities, indicating potential therapeutic effects in treating tonsillitis and dyspepsia. This study employed a network pharmacology approach to elucidate the shared mechanisms of CSG in the treatment of tonsillitis and dyspepsia. First, potential targets of CSG were predicted. Second, disease-related genes for tonsillitis and dyspepsia were retrieved from public databases. Third, a protein-protein interaction network was constructed and analyzed using gene ontology and Kyoto encyclopedia of genes and genomes. Finally, molecular docking was performed to validate key targets. The main active components of CSG included tectoridin, tectorigenin, rhamnocitrin, and rhamnazin, with 1148 key targets identified. We found 14 shared target genes between CSG and the 2 diseases. Using Cytoscape for analysis, we created a network diagram with 66 nodes. Molecular docking revealed that serine/threonine-protein kinase 1, mitogen-activated protein kinase 1, epidermal growth factor receptor, vascular endothelial growth factor A, and phosphoinositide-3-kinase regulatory subunit 1 are likely involved in CSG's multi-target effects. The potential pathways of CSG in treating tonsillitis and dyspepsia involve the regulation of endogenous deoxyribonuclease activity, nucleotide excision repair, and DNA damage recognition, among other biological processes. These findings suggest that CSG's potential effects on tonsillitis and dyspepsia may involve multi-compound, multi-target, and multi-pathway mechanisms, providing preliminary mechanistic insights for future research.

Acacetin, a naturally occurring flavonoid, has attracted increasing attention due to its broad anticancer potential. In vitro and in vivo studies using diverse tumor models have demonstrated that acacetin modulates oncogenic signaling, suppresses angiogenesis, and induces apoptosis and other regulated cell death pathways. With the rising demand for multi-target therapeutics, network pharmacology and molecular docking have emerged as powerful tools to unravel the complex molecular mechanisms of phytochemicals. Unlike previous reviews that have mainly focused on single pathways or limited cancer contexts, this review emphasizes novelty by integrating network pharmacology with molecular docking and explicitly linking these computational predictions to experimental validation, thereby identifying epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and the serine/threonine kinase AKT (also known as protein kinase B (PKB) as central experimentally supported targets. This integrative framework maps acacetin's multi-target anticancer mechanisms and clarifies its translational opportunities for future therapeutic development.

Background/Objectives: Allergic diseases (e.g., asthma, chronic urticaria) are increasing globally, but current anti-allergic drugs exhibit limitations in efficacy and safety. Traditional Chinese Medicine (TCM) emphasizes constitutional regulation for allergic diseases management. The allergic constitution prescription (ACP), a TCM formulation, lacks clear mechanistic insights. Methods: This study employs a novel network pharmacology approach integrating ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) to identify ACP’s chemical components and compare its mechanisms with anti-allergic drugs. Chemical components of ACP were analyzed via UHPLC-Q-TOF-MS/MS, and allergic disease-related targets were collected from public databases. Anti-allergic drug targets were intersected with ACP-disease targets to identify unique and common pathways. Molecular docking and dynamics simulations assessed binding affinity between key compounds and core targets. Results: We identified 126 compounds in ACP. Compared to anti-allergic drugs, ACP targeted 10 unique and five common key pathways (e.g., MAPK signaling), 10 unique and nine common core targets (e.g., Tumor Necrosis Factor (TNF), IL-6), and 14 unique and 15 common key compounds. Simulations confirmed high binding affinity of ACP compounds to core targets. Conclusions: These findings highlight ACP’s potential multi-target mechanisms for allergic diseases treatment, identifying unique and shared pathways, targets, and compounds compared to anti-allergic drugs, offering new insights for further mechanistic studies. However, it is crucial to note that these mechanistic predictions and compound-target interactions are primarily derived from computational analyses, and experimental validation (e.g., in vitro or in vivo assays) is essential to confirm these computational findings.

The rise of Vancomycin-Resistant Enterococcus (VRE) has become a major public health concern due to its resistance to conventional antibiotics and ability to form biofilms. The urgent need for novel therapeutic strategies has led to increased interest in natural compounds with antimicrobial potential. Pubescine (PBN), a steroidal alkaloid isolated from Holarrhena pubescens, has demonstrated antimicrobial properties, but its efficacy against VRE remains unexplored. PBN was isolated and purified from Holarrhena pubescens using chromatographic techniques and identified through spectroscopic analysis. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) were determined via broth microdilution assays. Time-kill assays assessed the bacteriostatic or bactericidal nature of PBN. Resistance development was evaluated through prolonged bacterial exposure to subinhibitory concentrations. Synergistic interactions with vancomycin and cefoxitin were analyzed using checkerboard microdilution assays. Biofilm formation and eradication were assessed via crystal violet staining and fluorescence imaging. Metabolic activity and oxidative stress induction were measured using the Alamar Blue assay and Reactive Oxygen Species (ROS) quantification, respectively. PBN exhibited concentration-dependent inhibition of VRE growth, primarily exerting a bacteriostatic effect without promoting the development of resistance. Checkerboard assays revealed strong synergy between PBN and vancomycin (FICI = 0.1875) and cefoxitin (FICI = 0.3125), suggesting that PBN enhances the efficacy of these antibiotics. PBN significantly reduced biofilm formation and facilitated biofilm disruption at concentrations as low as 4 μg/mL. Metabolic assays demonstrated that PBN suppresses bacterial metabolic activity, while ROS quantification indicated a substantial increase in oxidative stress, suggesting a multi-targeted mechanism of action. These findings establish PBN as a promising antimicrobial agent with potent activity against vancomycin-resistant Enterococcus faecalis. Its ability to enhance antibiotic efficacy, inhibit biofilm formation, and induce oxidative stress underscores its potential as a novel therapeutic strategy against multidrug-resistant infections. Further in vivo studies and pharmacokinetic evaluations are warranted to assess its clinical applicability.

Alcoholic liver disease: Mechanistic insights and therapeutic potential of traditional Chinese medicine through preclinical and clinical evidence.

Glehniae Radix (GR) is primarily produced in Laiyang and Chifeng. It is a functional food with therapeutic and health-promoting effects due to its antioxidant and anti-inflammatory properties. However, the current standards only stipulate authentication criteria, without establishing a comprehensive evaluation framework to systematically enhance the quality control of GR. This study aimed to establish a "chemical-mechanism" quality control framework for GR through a three-tiered strategy: "chemical composition analysis-bioactivity quantification-mechanism network validation." Initially, UPLC fingerprints of 14 GR batches were constructed, and their antioxidant and anti-inflammatory activities were evaluated. Multivariate statistical models combined with activity indices were employed to optimize spectrum-effect relationships using a random forest algorithm, predicting bioactive constituents. Network pharmacology, molecular docking, and dynamics simulations were integrated to elucidate multi-component, multi-target, and multi-pathway mechanisms. Chemometric analysis identified imperatorin as a marker for quantifying differences between Laiyang and Chifeng origins. Pharmacodynamic assays confirmed GR's antioxidant and anti-inflammatory efficacy. Random forest-optimized spectrum-effect modeling prioritized falcarindiol and panaxynol as bioactive markers. Network pharmacology predicted GR's regulation of EGFR tyrosine kinase inhibitor resistance and ErbB signaling via targets (EGFR, PTGS2, NFKB1). Molecular docking revealed strong binding affinity (e.g., imperatorin-EGFR: -9.046 kcal mol-1), and dynamics simulations confirmed complex stability. Thus, imperatorin, falcarindiol, and panaxynol were prioritized as quality markers. This study establishes a data-driven framework linking GR's chemical composition to antioxidant/anti-inflammatory mechanisms, advancing batch consistency control and precision applications in clinical disorders.

ABSTRACT Ovarian cancer remains a leading cause of gynecological cancer mortality, highlighting the urgent need for novel therapeutics. Annona cherimola (AC), long recognized for its medicinal uses, is underexplored for anticancer potential. This study employed an integrative computational strategy—combining network pharmacology, molecular docking, and molecular dynamics (MD) simulations—to elucidate the multi-target mechanisms of AC phytochemicals against ovarian cancer. Twenty bioactive compounds, mainly acetogenins, alkaloids, and phenolics, were identified, with 312 overlapping targets mapped to ovarian cancer genes. Protein–protein interaction analysis revealed hub genes including STAT3, NFKB1, and MTOR, while enrichment analyses linked them to key oncogenic and immune pathways. Docking and 200 ns MD simulations with MM/GBSA calculations demonstrated strong and stable interactions, with Anonaine and Liriodenine showing superior binding to reference inhibitors. These compounds appear to regulate signaling cascades associated with tumor progression, immune evasion, and therapy resistance. Overall, this work provides compelling in silico evidence for the multi-targeted anticancer potential of AC phytoconstituents, establishing a strong foundation for experimental validation and positioning AC as a promising source of candidate agents for ovarian cancer therapy.

Angelica sinensis and Scutellaria baicalensis synergistically alleviates metabolic dysfunction-associated steatohepatitis via promoting adipose tissue-to-liver tissue communication.

IntroductionHypertensive nephropathy (HN) is a common complication of hypertension. Clinically, there is an urgent need for new HN treatment strategies. Sijunzitang (SJZT) is widely used in clinical practice, but its therapeutic effects and pharmacological mechanisms in the treatment of HN remain unclear.MethodsThe active components, key targets, and potential pharmacological mechanisms of SJZT in treating HN were investigated through mass spectrometry, network pharmacology, and molecular docking. Subsequently, we validated the therapeutic effects of SJZT and the potential mechanisms using an Angiotensin II (Ang II)-induced HN mouse model and primary renal fibroblasts in vitro.ResultsNetwork pharmacology identified 87 active components and 26 potential therapeutic targets of SJZT in treating HN, among which PPARγ, TNF, CRP, ACE, and HIF-1α were identified as key targets. Molecular docking demonstrated strong binding affinity between the core active components (Licoisoflavone B, Glabrone, and Frutinone A) and PPARγ. Animal experiments revealed that SJZT attenuated renal damage and extracellular matrix deposition in HN model mice. In vitro experiments revealed that SJZT suppressed Ang II-induced renal fibroblasts activation, as evidenced by reduced cell viability, α-SMA, and Collagen I expression. Mechanistically, SJZT alleviated hypertensive renal fibrosis through PPARγ upregulation in renal fibroblasts, subsequently inducing autophagy activation.ConclusionThis preclinical study establishes that SJZT ameliorates HN through a multi-component, multi-target, and multi-pathway mechanism. Key findings confirm that SJZT activates autophagy via PPARγ upregulation, which subsequently inhibits renal fibroblast activation and attenuates HN progression. These results provide a pharmacological foundation for the translational application of SJZT in HN treatment.

This study investigated the potential of the deep-sea-derived fungal metabolite, chlorinated azaphilone compound chaetomugilin O, in the treatment of thyroid cancer. Chaetomugilin O was extracted from the fungus Chaetomium globosum YP-106 and subjected to in vitro experiments. The results demonstrated that this compound significantly inhibited the proliferation of thyroid cancer CAL-62 cells in a dose-dependent manner, with an IC50 value of 13.57 µM. Further mechanistic studies revealed that chaetomugilin O exerts its antitumor effects by inducing reactive oxygen species (ROS) accumulation, G2/M phase cell cycle arrest, and apoptosis. Transcriptomic analysis indicated its regulatory role in the PI3K-Akt signaling pathway, suggesting a multi-target synergistic antitumor mechanism. Molecular docking confirmed that chaetomugilin O binds to the Akt protein, forming a hydrogen bond with Lys158, implying its potential to directly inhibit Akt activity and interfere with PI3K-Akt pathway function. This study provides experimental evidence for the development of novel, low-toxicity, highly effective therapeutic agents for thyroid cancer.

Isoliquiritigenin micellar microneedle for pH monitoring and diabetic wound healing

As a global public health challenge, ocular diseases are driven by interconnected mechanisms, including oxidative stress, vascular abnormalities, and neurodegeneration. This review analyzes the multitarget mechanisms of berry-derived bioactive components (anthocyanins, proanthocyanidins, vitamin C, lutein, zeaxanthin, quercetin, and resveratrol) in regulating ocular homeostasis. Beyond antioxidant and anti-inflammatory effects, these compounds delay the progression of age-related macular degeneration, diabetic retinopathy, and glaucoma through mechanisms such as improving microcirculation, protecting photoreceptors, modulating angiogenesis, and inhibiting advanced glycation end-product deposition. Their protective effects involve the synergistic regulation of PI3K/AKT, Nrf2/HO-1, and VEGF pathways, supporting berry-based nutritional interventions for ocular health. Bioavailability and metabolism of these compounds are also discussed, highlighting their translational potential for the prevention and adjunctive therapy of ocular diseases.

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and hepatic ectopic lipid deposition (ELD), poses a complex metabolic challenge. This study aimed to elucidate the mechanisms of Yiqi Huazhuo Decoction (YD) through an inte-grated approach combining network pharmacology and metabolomics. T2DM is marked by impaired insulin signaling and disrupted hepatic lipid metabolism, resulting in a vicious cycle that accelerates disease progression. While Traditional Chinese Medicine (TCM), such as YD, demonstrates potential in modulating these dysfunctions, its underlying molecular mecha-nisms remain to be fully clarified. A diabetic fat rat model was used to evaluate the efficacy of YD. UPLC-MS characterized the main metabolites found in YD. After an 8-week intervention, physiological indices and hepatic pathology were assessed. Network pharmacology identified bioactive metabolites and targets, which were validated by molecular docking. Untargeted metabolomics was employed to analyze hepatic metabolic changes. YD improved glucose/lipid metabolism, insulin sensitivity, and hepatic function. Net-work pharmacology revealed that YD acts via the EGFR and PI3K-Akt/IL-17 pathways. Mo-lecular docking confirmed luteolin-EGFR binding. Metabolomics identified 20 altered metab-olites in the biosynthesis of unsaturated fatty acids. Multi-omics analysis revealed that YD regulated EGFR and hepatic metabolic networks. The multi-metabolite, multi-target mechanism of YD distinguishes it apart from single-target drugs, such as metformin. The binding of luteolin to EGFR may potentially re-activate the PI3K-Akt signaling pathway, thereby enhancing insulin sensitivity. Regulation of metabolic pathways, including the biosynthesis of unsaturated fatty acids, contributes to the reduction of hepatic lipid deposition. These findings underscore the capacity of YD to disrupt the IR-ELD cycle in T2DM. YD ameliorates T2DM-IR and hepatic ELD by modulating EGFR signaling and metabolic pathways, providing multi-omics evidence for its clinical application.

Nasopharyngeal carcinoma (NPC) is highly sensitive to radiotherapy, which, however, may trigger complications such as radiation-induced sinusitis (RIS) to impair patients' quality of life. Modified Sijunzi decoction (SJZD), a traditional Chinese medicine (TCM) formulation, has been revealed to exert therapeutic potential in RIS prevention and management. However, at this stage, we know little about its specific composition and molecular mechanism, which was a focus of our current study. This cross-sectional study was conducted on 86 NPC patients treated at our institution between August 2019 and August 2022. This study further assessed the association between TCM use and RIS incidence by using univariate analysis and multivariate logistic regression. Association rule mining and cluster analysis were employed to identify modified SJZD as the core prescription. Network pharmacology analysis was further applied to elucidate its mechanism of action. Univariate analysis demonstrated that TCM exposure was associated with reduced RIS prevalence (55.81%) (P = 0.002), and binary logistic regression analysis confirmed TCM use as an independent protective factor against RIS development (P = 0.001, OR = 0.156, 95% CI: 0.050-0.487). Furthermore, cluster analysis and association rule mining indicated that modified SJZD emerged as the core therapeutic prescription. Network pharmacology analysis identified 67 potential molecular targets of modified SJZD in RIS treatment. In addition, KEGG pathway enrichment revealed that modified SJZD exerted its therapeutic effects through multi-target mechanisms, particularly involving pathways in cancer, microRNAs in cancer, the JAK-STAT signaling pathway, and the NF-κB signaling pathway. There is a potential inverse association between TCM use and RIS incidence. Modified SJZD is identified as the core therapeutic formula, which appears to exert its protective effects through multiple bioactive components, diverse molecular targets, and multiple pathways.