Chemical Biology & Drug Design最新文献

{"title":"Application of Systems Genetics to Investigate Molecular Pathology of Early-Onset Colorectal Cancer","authors":"Minjae J. Kim,&nbsp;Sydney L. Carr,&nbsp;Vishnutheertha Kulkarni,&nbsp;Mary-Louise Manchadi","doi":"10.1111/cbdd.70379","DOIUrl":"10.1111/cbdd.70379","url":null,"abstract":"<p>Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the United States. The incidence of early-onset CRC (EOCRC) has been rising in the past few decades. Given the multifaceted nature of EOCRC, the genetic and environmental factors contributing to this malignancy have remained elusive. Systems genetics is a multi-omics tool that analyzes multiple genes as a collective network. Transcriptional correlation, protein–protein interaction network, functional annotation, and drug-gene interaction analyzes enable investigators to explore the functional roles of target genes and aid with discovery of novel diagnostic biomarkers and potential therapeutics. To clarify the objective of this work, this manuscript serves three purposes: a narrative review of recent systems genetics applications in EOCRC research, a step-by-step protocol for conducting these analyses, and a discussion of current advances in systems genetics to address limitations in generalizability and context dependence. Through this manuscript, we envision a future in which emerging oncology researchers adopt these tools into their investigations of EOCRC and other malignancies.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70379","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-Cancer Multi-Omics Analysis Reveals the Potential of ZDHHC16 in Tumor Progression and Immune Regulation","authors":"Haolong Zhang,&nbsp;Sen Wu,&nbsp;Yufei Ma,&nbsp;Yufei Yang,&nbsp;Yixin Zhang,&nbsp;Xue Hai Liu,&nbsp;Haoling Zhang,&nbsp;Zheng Zhang","doi":"10.1111/cbdd.70355","DOIUrl":"10.1111/cbdd.70355","url":null,"abstract":"<div>\u0000 \u0000 <p>S-palmitoylation is a crucial post-translational modification that regulates diverse cellular processes, particularly signalling pathways. The ZDHHC family of enzymes catalyzes this modification, however, the role of ZDHHC16 in cancer warrants in-depth investigation. This study presents a comprehensive pan-cancer analysis of ZDHHC16, examining its expression patterns, clinical relevance, associations with immune responses, genomic characteristics, and potential as a therapeutic target. We further analysed single-cell and spatial transcriptomic data to identify specific cell populations associated with ZDHHC16 dysregulation. Our findings reveal that ZDHHC16 dysregulation is tissue-specific and promotes tumor progression and modulates immune responses, highlighting its potential as a therapeutic target in several cancers, including ACC and BRCA. In ACC and BRCA, high ZDHHC16 expression correlates with shorter overall survival (<i>p</i> &lt; 0.001) and regulates PD-L1 expression.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148703038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pomegranate Peel Polyphenol Extract Ameliorates Hyperuricemia by Inhibiting Uric Acid Synthesis and Reabsorption","authors":"Zeyu Yin,&nbsp;Shufei Liang,&nbsp;Gangao Yang,&nbsp;Pingping Guo,&nbsp;Chao Wang,&nbsp;Qingqing Han,&nbsp;Xinhua Song","doi":"10.1111/cbdd.70376","DOIUrl":"10.1111/cbdd.70376","url":null,"abstract":"<p>Hyperuricemia (HUA) is a common metabolic disorder with limited safe and effective therapeutic options. This study integrated GEO dataset mining and network pharmacology to explore the anti-HUA efficacy and mechanism of pomegranate peel polyphenol extract (PPE). In a mouse model of HUA induced by potassium oxonate and 5% fructose water, PPE significantly reduced serum, urinary, and fecal uric acid levels, attenuated the increases in creatinine and blood urea nitrogen, improved estimated glomerular filtration rate, and ameliorated renal pathological damage, inflammation, and xanthine oxidase activity. Integration of GEO-derived HUA-related genes and computational target prediction for PPE identified 44 common targets, and protein–protein interaction network analysis revealed core targets including Akt1. KEGG enrichment highlighted the PI3K-AKT signaling pathway as a key mediator. Western blotting in vivo and in vitro confirmed that PPE suppressed PI3K-AKT phosphorylation and downregulated the urate reabsorption transporters URAT1 and GLUT9. Furthermore, experiments in UA-induced HK-2 cells demonstrated that ellagic acid, a major bioactive component of PPE, acted through the same pathway. These findings indicate that PPE reduces uric acid levels and protects the kidney via modulation of the PI3K-AKT pathway, providing an integrative data-driven rationale for its potential as a functional food or pharmaceutical agent against HUA.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13444214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148681445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational Design, Synthesis, and Biological Evaluation of New Substituted Dihydropyrimidinones as Antibacterial Agents and β-Lactamase Inhibitors","authors":"Ahmed M. Soliman,&nbsp;Heba Abdelrasheed Allam,&nbsp;Walaa R. Mahmoud,&nbsp;Bassem H. Naguib","doi":"10.1111/cbdd.70374","DOIUrl":"10.1111/cbdd.70374","url":null,"abstract":"<p>A series of new substituted 1,6-dihydropyrimidinones was designed, synthesized, and biologically evaluated as potential antibacterial candidates and <i>β</i>-lactamase enzyme inhibitors. All the synthesized compounds were tested for their antibacterial activity against <i>Staphylococcus aureus, Bacillus subtilis</i> as a gram-positive species whereas <i>Pseudomonas aeruginosa</i> as a gram-negative species was utilized. Most of the compounds exhibited moderate antibacterial activity compared to the reference drug amoxicillin. Furthermore, clinical antibacterial tests were conducted on <i>β</i>-lactamase resistant strains, including <i>Acinetobacter baumannii, Bacillus subtilis</i>, and <i>Staphylococcus aureus</i>. Results indicated that the candidate compounds possess potentiation effect, indicating their role as effective <i>β</i>-lactamase enzyme inhibitors. Whereas <i>in-vitro</i> assay performed on <i>β</i>-lactamase enzymes revealed that compounds <b>3d</b>, <b>3i</b>, and <b>7b</b> (IC₅₀ = 0.758, 0.400, and 0.524 nM) have lower IC₅₀ values compared to clavulanic acid (IC₅₀ = 0.934 nM). These findings suggested that compounds <b>3d</b>, <b>3i</b>, and <b>7b</b> are considered as promising hits for further exploration of potent and selective <i>β</i>-lactamase inhibitors.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13438106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in Conjugation Chemistry Expanding the Applications of the DNA Tetrahedron","authors":"Tyler J. Rutherford,&nbsp;Christopher J. Wilds","doi":"10.1111/cbdd.70369","DOIUrl":"10.1111/cbdd.70369","url":null,"abstract":"<p>The tetrahedral DNA nanostructure (TDN) has emerged as a premier, highly programmable framework for targeted drug delivery and diagnostics. This review provides a definitive, chemistry-first design guide for TDN engineering, systematically structured across three translational tiers. First, we examine foundational derivatives, detailing how precise modifications across the three components of the nucleotide scaffold confer essential nuclease resistance and structural longevity. Second, a diverse array of conjugation strategies is compiled, mapping the chemical mechanics of stable and responsive covalent linkages alongside distinct non-covalent loading modalities, including intercalation, metallo-coordination, and groove binding. Third, we explore advanced derivatives for materials science, detailing how merging TDNs with traditional nanotechnology or smart polymeric matrices yields hybrid architectures engineered into sophisticated analytical tools and biomaterials. Advancing this platform will entail integration of AI-driven computational models and navigating critical physiological barriers, establishing the functionalized TDN as a definitive cornerstone of next-generation nanomedicine.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13438694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-Omics Integration Reveals That SN-011 Targets JUNB to Upregulate ADGRE5 and Restore Vascular Endothelial Cell Communication in Ischemic Stroke","authors":"XiangLing Ou,&nbsp;ZunKe Gong","doi":"10.1111/cbdd.70363","DOIUrl":"10.1111/cbdd.70363","url":null,"abstract":"<p>Ischemic stroke (IS) is a cerebrovascular disease with high mortality and disability rates, currently lacking effective therapeutic targets. The STING inhibitor SN-011 shows potential in IS treatment, but its mechanism of action remains unclear. This study aims to explore the key molecular mechanisms of SN-011 in treating IS through bioinformatics approaches. IS transcriptome datasets were analyzed to identify differentially expressed genes. Mendelian randomization using brain eQTL and IS-GWAS data identified genes with causal relationships to IS. Single-cell transcriptome, pseudo-time trajectory, intercellular communication, and transcription factor regulatory network analyzes were performed. Molecular docking and DARTS-WB assay validated SN-011 binding to transcription factors. Transcriptomic analysis identified 77 intersecting genes. Mendelian randomization revealed ADGRE5 as a protective gene for IS (OR &lt; 1), significantly downregulated in venous endothelial cells (vECs) during disease progression. Cell communication analysis showed ADGRE5-high vECs interact with immune, glial, and stromal cells via LAMININ (Lamb2-CD44, Lamb2-Itga6+Itgb1, Lamb2-Dag1 pair) and JAM signaling pathways. Transcription factor analysis identified JUNB as a negative regulator of ADGRE5. Molecular docking (−6.8 kcal/mol) combined with an in vitro DARTS-WB assay confirmed the interaction between SN-011 and JUNB. In OGD-induced endothelial cell injury models, SN-011 suppressed JUNB expression, restored ADGRE5 expression inhibited by JUNB overexpression, reversed the downregulation of LAMB2 and CD44, and reduced the expression of the pro-inflammatory cytokines IL-6 and IL-1β. Notably, blockade of LAMB2 largely abolished these protective effects, indicating that the anti-inflammatory and endothelial-protective activities of SN-011 are mediated, at least in part, through restoration of the LAMB2-CD44 signaling axis. ADGRE5 downregulation in vECs may impair vascular repair by disrupting LAMININ-mediated intercellular communication. SN-011 may exert neuroprotective effects by targeting JUNB to upregulate ADGRE5 expression and restore the vEC-centered cellular communication network, providing a theoretical basis for SN-011 as a potential IS therapeutic.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Benzenesulfonylpiperazine Derivative With In Vivo Efficacy Against Visceral Leishmaniasis","authors":"Thibault Joseph William Jacques Dit Lapierre,&nbsp;Mariza Gabriela Faleiro de Moura Lodi Cruz,&nbsp;Guilherme Freitas de Lima Hercos,&nbsp;Rafael Consolin Chelucci,&nbsp;Simone Michelan-Duarte,&nbsp;Gisele Barbosa,&nbsp;Analu R. Costa,&nbsp;Miguel Angel Chávez-Fumagalli,&nbsp;Paula Derksen Macruz,&nbsp;Eduardo Jorge Pilau,&nbsp;Leonardo L. G. Ferreira,&nbsp;Adriano D. Andricopulo,&nbsp;Silvane Maria Fonseca Murta,&nbsp;Celso de Oliveira Rezende Júnior","doi":"10.1111/cbdd.70367","DOIUrl":"10.1111/cbdd.70367","url":null,"abstract":"<p>Benzenesulfonylpiperazines have been previously identified as a promising class against Chagas disease and leishmaniasis, two parasitic neglected tropical diseases. Thus, the pharmacokinetic profile of two potential leads against visceral leishmaniasis was assessed in vitro. Both lead candidates <b>1</b> and <b>2</b> exhibited a satisfactory ADME profile, with <b>2</b> proving slightly superior in terms of metabolic stability. Therefore, after complementary toxicity assessment which revealed that <b>2</b> did not exert hepatotoxicity in vitro or acute toxicity in vivo, the evaluation of its efficacy in a mouse model highlighted that <b>2</b> indeed displays antileishmanial efficacy in vivo. Albeit moderate at a dose of 50 mg/kg/day, its efficacy increased at a dose of 100 mg/kg/day, reducing the parasite burden by 90% in the spleen of infected mice, though safety concerns were raised at this dose. In vitro investigation of its mode of action revealed that <b>2</b> exerts a cytostatic effect on <i>Leishmania infantum</i> promastigotes, promoting cell cycle arrest during the G0/G1 phase which may potentially be linked to the production of reactive oxygen species.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148671569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin-Loaded GelMA Microspheres Alleviate Osteoarthritis: Transcriptomic Evidence for Immune Microenvironment Remodeling and ECM Homeostasis Restoration","authors":"Bin Jiang,&nbsp;Xin Jiang,&nbsp;Shaobo Li,&nbsp;Hao Niu,&nbsp;Wenbin Ji","doi":"10.1111/cbdd.70373","DOIUrl":"10.1111/cbdd.70373","url":null,"abstract":"<p>Osteoarthritis (OA) progression is driven by inflammatory mediators and immune dysregulation within the joint. Curcumin (Cur) possesses multi-target therapeutic potential. However, its clinical application is limited by poor solubility and a short half-life. In this study, we developed injectable Cur-loaded GelMA microspheres (Cur-MS) and evaluated their effects in IL-1β stimulated chondrocytes, cartilage organoids, and a monosodium iodoacetate (MIA) induced rat OA model, complemented by public transcriptomic analysis (GSE114007). The Cur-MS demonstrated uniform size distribution, favorable biocompatibility, and sustained curcumin release. Treatment with Cur-MS significantly reduced chondrocyte apoptosis, reactive oxygen species levels, and hypertrophic markers; restored COL-II and ACAN synthesis; and downregulated MMP13 and inflammatory gene expression. In vivo, Cur-MS improved joint space, alleviated pain, decreased synovial CD68 positive macrophage infiltration and levels of IL-6 and TNF-α, and enhanced chondrogenic gene expression. Public transcriptomic data corroborated these findings, revealing upregulation of MMP13 and downregulation of SOX9 in OA cartilage, consistent with our experimental targets. Collectively, this study provides the first multi-model evidence combined with transcriptomic validation, demonstrating that Cur-MS not only directly protects chondrocytes and restores extracellular matrix homeostasis but also modulates the joint inflammatory immune microenvironment. These findings suggest that Cur-MS represents a promising locally sustained-release therapeutic strategy for OA.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148665071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Artificial Intelligence Into Drug Discovery From Medicinal Plants: Current Applications and Infrastructural Challenges","authors":"Amit Gangwal,&nbsp;Azim Ansari,&nbsp;Mohd Usman Mohd Siddique,&nbsp;Jyotiram Sawale,&nbsp;Suhas Padmane,&nbsp;Raju Wadekar","doi":"10.1111/cbdd.70372","DOIUrl":"https://doi.org/10.1111/cbdd.70372","url":null,"abstract":"<p>Medicinal plants represent a vast and evolutionarily refined reservoir of structurally diverse bioactive compounds that have historically contributed to major therapeutic breakthroughs. However, despite their pharmacological richness, systematic translation of plant-derived metabolites into clinically approved drugs remains constrained by persistent bottlenecks, including extract complexity, dereplication redundancy, structural elucidation challenges, taxonomic ambiguity, and multi-component pharmacology. This review presents a bottleneck-driven and systems-oriented framework for integrating artificial intelligence (AI) into medicinal plant-based drug discovery (MPDD) to address some of these bottlenecks. Rather than reiterating broadly documented AI tools used in synthetic drug development, the manuscript critically examines phytomedicine-specific challenges and maps AI applications across key stages of the pipeline: medicinal plant identification, extraction optimization, plant metabolite identification and dereplication, absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction, virtual screening, network pharmacology, repurposing, and generative de novo design of pseudo-natural products. Emphasis is placed on the foundational requirement of making phytochemical datasets truly AI-ready through metadata harmonization, dataset balancing, novelty-aware modeling, and structured data engineering. Emerging approaches such as transformer-based foundational models, graph neural networks (GNNs), generative AI (GAI) architectures, and multi-omics-integrated network pharmacology are discussed within a pragmatic translational context. Importantly, this review maintains a balanced perspective, acknowledging that fully AI-driven clinically approved botanical drugs/synthetic drugs have yet to emerge and identifies challenges limiting the progress. By integrating computational methods with infrastructural reform, this work outlines a progressive roadmap to transition AI in medicinal plant research from exploratory studies toward standardized, reproducible, and biologically grounded next-generation drug discovery.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Jiuwei Xiaozhi Decoction Alleviates High-Fat Diet-Induced MASLD by Suppressing Hepatic SREBP2-Driven Cholesterogenesis and Restoring PPARα-Mediated Fatty Acid Oxidation","authors":"Youcheng Ma,&nbsp;Xinrui Gao,&nbsp;Ji Wang,&nbsp;Lingru Li,&nbsp;Zhen Huang,&nbsp;Fangli Li","doi":"10.1111/cbdd.70371","DOIUrl":"10.1111/cbdd.70371","url":null,"abstract":"<p>Jiuwei Xiaozhi Decoction (JWXZ) is a nine-herb traditional Chinese medicine formula clinically used for hepatic steatosis and dyslipidemia, but its chemical basis and pharmacological mechanisms in metabolic dysfunction-associated steatotic liver disease (MASLD) remain incompletely defined. The chemical profile of JWXZ was characterized by UHPLC-HRMS/MS. Its therapeutic effects were evaluated in a high-fat diet (HFD)-induced mouse model of MASLD, followed by hepatic transcriptomic analysis, network pharmacology, molecular docking, Western blotting, and immunofluorescence validation. UHPLC-HRMS/MS identified 178 chemical constituents in JWXZ, including phenolic acids, flavonoids, flavonoid glycosides, alkaloids, isoflavones, and coumarins. In HFD-fed mice, JWXZ attenuated body weight gain, white adipose accumulation, dyslipidemia, hepatic triglyceride and cholesterol accumulation, serum transaminase elevation, and hepatic steatosis, while improving glucose tolerance and partially restoring whole-body metabolic flexibility. Hepatic transcriptomics identified 124 HFD-dysregulated genes reversed by high-dose JWXZ, with prominent enrichment in cholesterol and sterol biosynthesis, endoplasmic reticulum proteostasis, oxidative stress response, and PPARα-related lipid handling. Integrated transcriptomic and network pharmacology analyses further identified 157 shared targets and 18 overlapping pathways, converging mainly on cholesterol metabolism and PPAR signaling. Protein-level validation showed that JWXZ suppressed SREBP2 proteolytic activation, reduced nuclear SREBP2 abundance, and downregulated HMGCR, SQLE, and PCSK9, indicating inhibition of the hepatic cholesterogenic program. In parallel, JWXZ restored nuclear PPARα abundance and CPT1A expression, consistent with reactivation of fatty acid oxidation. JWXZ also reduced hepatic EGFR phosphorylation and lowered hepatic and circulating TNF-α, IL-6, IL-1β, and MCP-1 levels. Molecular docking provided supportive evidence for potential interactions between representative JWXZ constituents and key regulators, including naringin-HMGCR, chlorogenic acid-SQLE, rhoifolin-PPARα, and rhoifolin-SREBP2. These findings suggest that JWXZ ameliorates HFD-induced MASLD mainly by rebalancing hepatic lipid metabolism through coordinated suppression of SREBP2-mediated cholesterogenesis and restoration of PPARα-mediated fatty acid oxidation, with associated attenuation of EGFR-linked inflammatory responses.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"108 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148611016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}