{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:45:58Z","timestamp":1787161558934,"version":"build-2736575974"},"reference-count":44,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82374311"],"award-info":[{"award-number":["82374311"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82374311"],"award-info":[{"award-number":["82374311"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"crossref","award":["ZR2022LZY016"],"award-info":[{"award-number":["ZR2022LZY016"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Research and Development Program Foundation of Shandong Province","award":["2022CXGC020514"],"award-info":[{"award-number":["2022CXGC020514"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen that poses a major public health concern. It predominantly infects immunocompromised individuals and is frequently associated with severe pulmonary complications, including acute lung injury. Diosmetin, a natural flavonoid, known for its anti-inflammatory, antioxidant, and anti-infective properties. Nevertheless, its therapeutic mechanism in the treatment of acute pneumonia induced by MRSA remains unclear. Methods: In this study, we employed network pharmacology and molecular docking to elucidate the mechanisms underlying the therapeutic effect of diosmetin against MRSA-induced pneumonia. An MRSA pneumonia model was established in Balb\/c mice. The impacts of diosmetin on murine pneumonia were evaluated by detecting biochemical indicators via HE staining, ELISA, RT-qPCR, and WB. In vitro experiments utilized RAW264.7 macrophages to establish an MRSA infection model for further validation of the therapeutic mechanisms of diosmetin. Results: In vivo results demonstrated that diosmetin alleviated MRSA-induced lung injury and reduced mortality by inhibiting the release of pro-inflammatory cytokines. Furthermore, compared with model mice, diosmetin-treated mice showed reduced phosphorylation levels of NLRP3, pro-caspase-1, ASC, and NF-\u03baB p65, along with an increased level of I\u03baB\u03b1 in lung tissue. In vitro experiments indicated that diosmetin effectively reduced the levels of pro-inflammatory cytokines in MRSA-infected RAW264.7 macrophages and exerted anti-inflammatory effects by modulating the expression of NLRP3, pro-caspase-1, ASC, I\u03baB\u03b1, and NF-\u03baB p65. Conclusions: Our results demonstrate that diosmetin alleviates MRSA-induced pneumonia in mice, and this protective effect is achieved through dual inhibition of the NF-\u03baB\/NLRP3 inflammasome axis.<\/jats:p>","DOI":"10.3390\/ph19050674","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T10:34:42Z","timestamp":1777458882000},"page":"674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diosmetin Alleviates MRSA-Induced Pneumonia in Mice by Inhibiting NLRP3 Inflammasome Activation and NF-\u03baB Signaling Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Chenxi","family":"Wu","sequence":"first","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiguo","family":"Xie","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofei","family":"Liang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lujie","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxiao","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wu","sequence":"additional","affiliation":[{"name":"Clinical Laboratory, Changqing District People\u2019s Hospital, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6278","DOI":"10.1128\/JB.185.21.6278-6286.2003","article-title":"Molecular architecture of the regulatory Locus sae of Staphylococcus aureus and its impact on expression of virulence factors","volume":"185","author":"Steinhuber","year":"2003","journal-title":"J. Bacteriol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e00020-18","DOI":"10.1128\/CMR.00020-18","article-title":"Methicillin-Resistant Staphylococcus aureus: Molecular Characterization, Evolution, and Epidemiology","volume":"31","author":"Lakhundi","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41579-018-0147-4","article-title":"Methicillin-resistant Staphylococcus aureus: An overview of basic and clinical research","volume":"17","author":"Turner","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"De Vita, E., Segala, F.V., Cavallin, F., Guido, G., Frallonardo, L., Cotugno, S., Pellegrino, C., Di Gennaro, F., and Saracino, A. (2024). Rapid de-escalation of anti-MRSA therapy guided by S. aureus nares screening for patients with pneumonia: Protocol of a randomized controlled trial (SNAP study). Front. Med., 11.","DOI":"10.3389\/fmed.2024.1416904"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Pak, S., Thapa, B., and Lee, K. (2021). Decursinol Angelate Mitigates Sepsis Induced by Methicillin-Resistant Staphylococcus aureus Infection by Modulating the Inflammatory Responses of Macrophages. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222010950"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"117997","DOI":"10.1016\/j.ecoenv.2025.117997","article-title":"Diosmetin alleviates AFB1-induced endoplasmic reticulum stress, autophagy, and apoptosis via PI3K\/AKT pathway in mice","volume":"292","author":"Li","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112248","DOI":"10.1016\/j.intimp.2024.112248","article-title":"Diosmetin ameliorates psoriasis-associated inflammation and keratinocyte hyperproliferation by modulation of PGC-1\u03b1\/YAP signaling pathway","volume":"134","author":"Yang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Pan, Y., Sun, R., Thomas, E.R., Pan, S., Yang, L., Wang, W., Chen, L., and Li, X. (2026). Diosmetin, an active ingredient of Schizonepeta tenuifolia, alleviates acne by regulating inflammation and oxidative stress. Naunyn Schmiedeberg\u2019s Arch. Pharmacol., Online ahead of print.","DOI":"10.1007\/s00210-026-05101-6"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.12659\/MSM.911860","article-title":"Diosmetin Suppresses Neuronal Apoptosis and Inflammation by Modulating the Phosphoinositide 3-Kinase (PI3K)\/AKT\/Nuclear Factor-\u03baB (NF-\u03baB) Signaling Pathway in a Rat Model of Pneumococcal Meningitis","volume":"25","author":"Zhang","year":"2019","journal-title":"Med. Sci. Monit."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.molcel.2019.07.007","article-title":"\u03b1-Ketoglutarate-Activated NF-\u03baB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development","volume":"76","author":"Wang","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1080\/21505594.2021.1878688","article-title":"Pathogenicity and virulence of Staphylococcus aureus","volume":"12","author":"Cheung","year":"2021","journal-title":"Virulence"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1146\/annurev-biophys-083012-130338","article-title":"Molecular basis of NF-\u03baB signaling","volume":"42","author":"Napetschnig","year":"2013","journal-title":"Annu. Rev. Biophys."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Li, Y., Xia, Y., Yin, S., Wan, F., Hu, J., Kou, L., Sun, Y., Wu, J., Zhou, Q., and Huang, J. (2021). Targeting Microglial \u03b1-Synuclein\/TLRs\/NF-kappaB\/NLRP3 Inflammasome Axis in Parkinson\u2019s Disease. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.719807"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/s41419-020-03178-2","article-title":"Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-\u03baB\/NLRP3-mediated epithelial-mesenchymal transition and inflammation","volume":"11","author":"Peng","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/cmi.2015.95","article-title":"Molecular mechanisms regulating NLRP3 inflammasome activation","volume":"13","author":"Jo","year":"2016","journal-title":"Cell. Mol. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/crj.12134","article-title":"Consensus statement on the management of methicillin-resistant Staphylococcus aureus nosocomial pneumonia in Asia","volume":"9","author":"Cao","year":"2015","journal-title":"Clin. Respir. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"114453","DOI":"10.1016\/j.celrep.2024.114453","article-title":"Extracellular vesicles from alveolar macrophages harboring phagocytosed methicillin-resistant Staphylococcus aureus induce necroptosis","volume":"43","author":"Bai","year":"2024","journal-title":"Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chen, Y.G., Zhang, Y., Deng, L.Q., Chen, H., Zhang, Y.J., Zhou, N.J., Yuan, K., Yu, L.Z., Xiong, Z.H., and Gui, X.M. (2016). Control of Methicillin-Resistant Staphylococcus aureus Pneumonia Utilizing TLR2 Agonist Pam3CSK4. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0149233"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.4049\/jimmunol.2100328","article-title":"IFN-\u03b3 Drives TNF-\u03b1 Hyperproduction and Lethal Lung Inflammation during Antibiotic Treatment of Postinfluenza Staphylococcus aureus Pneumonia","volume":"207","author":"Verma","year":"2021","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.2147\/JIR.S466737","article-title":"Zhike Erfang Alleviates MRSA-Induced Pneumonia by Inhibiting TRAF6 and Activating NLRP3 Inflammatory Body","volume":"18","author":"Zhang","year":"2025","journal-title":"J. Inflamm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"154475","DOI":"10.1016\/j.phymed.2022.154475","article-title":"Compound 511 ameliorates MRSA-induced lung injury by attenuating morphine-induced immunosuppression in mice via PI3K\/AKT\/mTOR pathway","volume":"108","author":"Li","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"156477","DOI":"10.1016\/j.phymed.2025.156477","article-title":"Dual role of Baimao-Longdan-Congrong-Fang in inhibiting Staphylococcus aureus virulence factors and regulating TNF-\u03b1\/TNFR1\/NF-\u03baB\/MMP9 axis","volume":"139","author":"Jiang","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s00430-023-00782-9","article-title":"Echinacoside, a promising sortase A inhibitor, combined with vancomycin against murine models of MRSA-induced pneumonia","volume":"212","author":"Jiang","year":"2023","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.micpath.2019.05.003","article-title":"Ginsenoside Rb1 ameliorates Staphylococcus aureus-induced Acute Lung Injury through attenuating NF-\u03baB and MAPK activation","volume":"132","author":"Shaukat","year":"2019","journal-title":"Microb. Pathog."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4988","DOI":"10.1002\/ptr.7131","article-title":"New perspectives on natural flavonoids on COVID-19-induced lung injuries","volume":"35","author":"Santana","year":"2021","journal-title":"Phytother. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1172\/JCI11830","article-title":"NF-kappaB: A key role in inflammatory diseases","volume":"107","author":"Tak","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"966","DOI":"10.4049\/jimmunol.2100283","article-title":"Lipoproteins from Staphylococcus aureus Drive Neutrophil Extracellular Trap Formation in a TLR2\/1- and PAD-Dependent Manner","volume":"207","author":"Hook","year":"2021","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41564-022-01278-7","article-title":"Staphylococcal virulence factor HlgB targets the endoplasmic-reticulum-resident E3 ubiquitin ligase AMFR to promote pneumonia","volume":"8","author":"Sun","year":"2023","journal-title":"Nat. Microbiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.7150\/ijbs.34211","article-title":"Caffeine Inhibits NLRP3 Inflammasome Activation by Suppressing MAPK\/NF-\u03baB and A2aR Signaling in LPS-Induced THP-1 Macrophages","volume":"15","author":"Zhao","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"155410","DOI":"10.1016\/j.phymed.2024.155410","article-title":"Protopine ameliorates OVA-induced asthma through modulatingTLR4\/MyD88\/NF-\u03baB pathway and NLRP3 inflammasome-mediated pyroptosis","volume":"126","author":"Yang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Tao, M., Chen, C., Zhao, X., Feng, Q., Chen, G., and Fu, Y. (2022). BAFF Blockade Attenuates DSS-Induced Chronic Colitis via Inhibiting NLRP3 Inflammasome and NF-\u03baB Activation. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.783254"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3660","DOI":"10.1002\/ptr.8214","article-title":"Diosmetin as a promising natural therapeutic agent: In vivo, in vitro mechanisms, and clinical studies","volume":"38","author":"Sun","year":"2024","journal-title":"Phytother. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"157","DOI":"10.4062\/biomolther.2016.234","article-title":"Diosmetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury through Activating the Nrf2 Pathway and Inhibiting the NLRP3 Inflammasome","volume":"26","author":"Liu","year":"2018","journal-title":"Biomol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/ptr.5098","article-title":"Flavonoids from Sophora moorcroftiana and their synergistic antibacterial effects on MRSA","volume":"28","author":"Wang","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s10482-015-0491-6","article-title":"Diosmetin inhibits the expression of alpha-hemolysin in Staphylococcus aureus","volume":"108","author":"Liu","year":"2015","journal-title":"Antonie Van Leeuwenhoek"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.phymed.2013.02.007","article-title":"Synergistic effects of diosmetin with erythromycin against ABC transporter over-expressed methicillin-resistant Staphylococcus aureus (MRSA) RN4220\/pUL5054 and inhibition of MRSA pyruvate kinase","volume":"20","author":"Chan","year":"2013","journal-title":"Phytomedicine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: A database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminform."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0168-9525(97)01103-7","article-title":"GeneCards: Integrating information about genes, proteins and diseases","volume":"13","author":"Rebhan","year":"1997","journal-title":"Trends Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"117321","DOI":"10.1016\/j.bcp.2025.117321","article-title":"Bavachinin exerts anti-tumor effects by activating TLR4\/STING axis-dependent PANoptosis and synergistically enhances chemosensitivity in endometrial cancer","volume":"242","author":"Shu","year":"2025","journal-title":"Biochem. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"157523","DOI":"10.1016\/j.phymed.2025.157523","article-title":"Tetrastigma hemsleyanum polysaccharides alleviate inflammatory bowel disease via the gut microbiota-SCFA-GPR43 signaling axis","volume":"149","author":"Lv","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"114105","DOI":"10.1016\/j.biopha.2022.114105","article-title":"Protective effects of CCL01 against A\u03b2-induced neurotoxicity in 5xFAD transgenic mouse model of Alzheimer\u2019s disease","volume":"158","author":"Ju","year":"2023","journal-title":"Biomed. Pharmacother."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/674\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T04:15:12Z","timestamp":1777522512000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/5\/674"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,25]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ph19050674"],"URL":"https:\/\/doi.org\/10.3390\/ph19050674","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,25]]}}}