{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:30:28Z","timestamp":1787585428387,"version":"build-2736575974"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100015800","name":"Jilin Provincial Development and Reform Commission","doi-asserted-by":"publisher","award":["2024C012-9"],"award-info":[{"award-number":["2024C012-9"]}],"id":[{"id":"10.13039\/100015800","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Hyperuricemia is a well-established risk factor for both chronic kidney disease and gout. Currently available urate-lowering drugs, however, are frequently compromised by hepatorenal toxicity and gastrointestinal adverse effects. Cinnamaldehyde, the principal bioactive constituent of the traditional Chinese medicine cinnamon, has documented renoprotective properties, yet its integrated effects on hyperuricemia-associated renal injury remain incompletely defined. Objectives: This study investigated the therapeutic effects of cinnamaldehyde on hyperuricemia and explored the molecular mechanisms involved. Materials and Methods: An in vivo hyperuricemia model was established in KM mice by co-administration of potassium oxonate and hypoxanthine for 14 consecutive days, and an in vitro injury model was generated by exposing HK-2 human renal tubular epithelial cells to uric acid. For the in vivo study, mice were divided into five groups (control, model, febuxostat, low-dose CA, and high-dose CA; n = 9 per group) and were treated by oral gavage. Serum biochemical indices, renal and intestinal histopathology, inflammatory cytokines, renal urate transporter proteins (OAT1, OCT2, ABCG2, and SLC2A9), and components related to AIF1 and CMPK2\/NLRP3 inflammasome signaling (ASC, caspase-1, IL-18, and IL-1\u03b2) were examined. Western blotting, qPCR, immunofluorescence, apoptosis analysis, mitochondrial membrane potential assessment, transmission electron microscopy, siRNA-mediated knockdown, and 16S rRNA gene sequencing were used to characterize the relevant mechanisms. Results: CA reduced serum uric acid (p \u2264 0.001 vs. model), creatinine (p \u2264 0.01 vs. model), and blood urea nitrogen (p \u2264 0.01 vs. model), alleviated renal and intestinal histopathological injury, and decreased circulating and renal inflammatory cytokines. Cinnamaldehyde increased ABCG2, OAT1, and OCT2 protein expression and reduced SLC2A9 expression (all p \u2264 0.05 vs. model). In vivo and in vitro, cinnamaldehyde suppressed AIF1- and CMPK2\/NLRP3-related inflammatory proteins, reduced uric acid-induced apoptosis, and preserved mitochondrial membrane potential and ultrastructure. Fecal 16S rRNA sequencing suggested changes in selected microbial taxa, although alpha-diversity and BrayCurtis-based PERMANOVA\/ANOSIM analyses did not demonstrate significant global community separation. Conclusions: These findings suggest that CA alleviates hyperuricemia-associated renal injury by regulating renal urate transporters, attenuating AIF1- and CMPK2\/NLRP3-related inflammatory signaling, accompanied by compositional shifts in selected gut microbial taxa that warrant further mechanistic investigation. The study provides experimental support for further evaluation of cinnamaldehyde as a multi-target candidate for hyperuricemia-related renal injury.<\/jats:p>","DOI":"10.3390\/ph19081261","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:10:24Z","timestamp":1786374624000},"page":"1261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cinnamaldehyde Attenuates Hyperuricemia-Associated Renal Injury by Modulating Urate Transporters and AIF1- and CMPK2\/NLRP3-Related Inflammatory Signaling"],"prefix":"10.3390","volume":"19","author":[{"given":"Yongxin","family":"Sun","sequence":"first","affiliation":[{"name":"College of Pharmacy, Beihua University, Jilin 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Tan","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Beihua University, Jilin 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Beihua University, Jilin 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Beihua University, Jilin 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Huai","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Beihua University, Jilin 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manli","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Beihua University, Jilin 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, Y., He, F., Yu, X., Li, T., Zhou, L., and Shen, B. (2025). Hyperuricemia-induced kidney injury: A narrative review of mechanisms and therapeutic advances. BMC Nephrol., 26.","DOI":"10.1186\/s12882-025-04414-7"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s11906-024-01295-3","article-title":"Hyperuricemia: An Intriguing Connection to Metabolic Syndrome, Diabetes, Kidney Disease, and Hypertension","volume":"26","author":"Vareldzis","year":"2024","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3892\/mmr.2024.13424","article-title":"Insights into renal damage in hyperuricemia: Focus on renal protection (Review)","volume":"31","author":"Yang","year":"2025","journal-title":"Mol. Med. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yanai, H., Adachi, H., Hakoshima, M., and Katsuyama, H. (2021). Molecular Biological and Clinical Understanding of the Pathophysiology and Treatments of Hyperuricemia and Its Association with Metabolic Syndrome, Cardiovascular Diseases and Chronic Kidney Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179221"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"150038","DOI":"10.1016\/j.bbrc.2024.150038","article-title":"Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice","volume":"716","author":"Fu","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.jare.2024.03.029","article-title":"Punicalagin attenuates hyperuricemia via restoring hyperuricemia-induced renal and intestinal dysfunctions","volume":"69","author":"Han","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Li, D., Yuan, S., Deng, Y., Wang, X., Wu, S., Chen, X., Li, Y., Ouyang, J., Lin, D., and Quan, H. (2023). The dysregulation of immune cells induced by uric acid: Mechanisms of inflammation associated with hyperuricemia and its complications. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1282890"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"18146","DOI":"10.1038\/s41598-024-69323-5","article-title":"LincRNA-p21\/AIF-1\/CMPK2\/NLRP3 pathway promoted inflammation, autophagy and apoptosis of human tubular epithelial cell induced by urate via exosomes","volume":"14","author":"Hao","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"De Leon-Oliva, D., Garcia-Montero, C., Fraile-Martinez, O., Boaru, D.L., Garc\u00eda-Puente, L., Rios-Parra, A., Garrido-Gil, M.J., Casanova-Mart\u00edn, C., Garc\u00eda-Honduvilla, N., and Bujan, J. (2023). AIF1: Function and Connection with Inflammatory Diseases. Biology, 12.","DOI":"10.3390\/biology12050694"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"123760","DOI":"10.1016\/j.lfs.2025.123760","article-title":"The axis of miR-30a\/AIF-1\/TRPC6\/calcineurin A\/NFAT2 regulated the death modalities and inflammation of renal tubular epithelial cells in diabetic kidney disease via exosome","volume":"377","author":"Hao","year":"2025","journal-title":"Life Sci."},{"key":"ref_11","first-page":"4033","article-title":"Aldosterone promotes renal interstitial fibrosis via the AIF-1\/AKT\/mTOR signaling pathway","volume":"20","author":"Yuan","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101522","DOI":"10.1016\/j.xcrm.2024.101522","article-title":"Microglial CMPK2 promotes neuroinflammation and brain injury after ischemic stroke","volume":"5","author":"Guan","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zheng, Y., Xie, Y., Li, J., Cao, Y., Li, M., Cao, Q., Han, M., Lou, H., Shu, Y., and Xiao, H. (2025). CMPK2 promotes NLRP3 inflammasome activation via mtDNA-STING pathway in house dust mite-induced allergic rhinitis. Clin. Transl. Med., 15.","DOI":"10.1002\/ctm2.70180"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s11658-023-00462-9","article-title":"The NLRP3 inflammasome: Contributions to inflammation-related diseases","volume":"28","author":"Chen","year":"2023","journal-title":"Cell Mol. Biol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/s41586-022-05570-8","article-title":"Cryo-EM structures of the active NLRP3 inflammasome disc","volume":"613","author":"Xiao","year":"2023","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"135550","DOI":"10.1016\/j.ijbiomac.2024.135550","article-title":"Effects and mechanisms of Polygonati Rhizoma polysaccharide on potassium oxonate and hypoxanthine-induced hyperuricemia in mice","volume":"280","author":"Zhang","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s40168-024-01826-9","article-title":"Gut microbiota dysbiosis in hyperuricaemia promotes renal injury through the activation of NLRP3 inflammasome","volume":"12","author":"Zhou","year":"2024","journal-title":"Microbiome"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12974-025-03373-y","article-title":"Cinnamaldehyde and its combination with deferoxamine ameliorate inflammation, ferroptosis and hematoma expansion after intracerebral hemorrhage in mice","volume":"22","author":"Liu","year":"2025","journal-title":"J. Neuroinflamm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107977","DOI":"10.1016\/j.micpath.2025.107977","article-title":"Cinnamomum zeylanicum essential oil inactivates Shigella flexneri by inhibiting biofilm formation, disrupting cell membrane integrity, and suppressing virulence gene expression","volume":"208","author":"Mohanty","year":"2025","journal-title":"Microb. Pathog."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Aggarwal, S., Bhadana, K., Singh, B., Rawat, M., Mohammad, T., Al-Keridis, L.A., Alshammari, N., Hassan, M.I., and Das, S.N. (2022). Cinnamomum zeylanicum Extract and its Bioactive Component Cinnamaldehyde Show Anti-Tumor Effects via Inhibition of Multiple Cellular Pathways. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.918479"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.micpath.2018.04.036","article-title":"Antibacterial mechanisms of cinnamon and its constituents: A review","volume":"120","author":"Vasconcelos","year":"2018","journal-title":"Microb. Pathog."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1080\/0886022X.2022.2056485","article-title":"Cinnamaldehyde attenuates kidney senescence and injury through PI3K\/Akt pathway-mediated autophagy via downregulating miR-155","volume":"44","author":"Xiao","year":"2022","journal-title":"Ren. Fail."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"139","DOI":"10.4103\/ejpi.EJPI-D-24-00017","article-title":"Cinnamaldehyde, a Bioactive Compound from the Leaves of Cinnamomum osmophloeum Kaneh, Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Inhibiting the NLRP3 Inflammasome","volume":"67","author":"Liu","year":"2024","journal-title":"J. Physiol. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tan, X., Wen, Y., Han, Z., Su, X., Peng, J., Chen, F., Wang, Y., Wang, T., Wang, C., and Ma, K. (2023). Cinnamaldehyde Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Modulating TLR4\/NF-\u03baB Signaling Pathway and NLRP3 Inflammasome Activation. Chem. Biodivers., 20.","DOI":"10.1002\/cbdv.202200089"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1093\/ndt\/gfv024","article-title":"Hyperuricemia-induced inflammasome and kidney diseases","volume":"31","author":"Isaka","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.phymed.2008.06.002","article-title":"Essential oil from leaves of Cinnamomum osmophloeum acts as a xanthine oxidase inhibitor and reduces the serum uric acid levels in oxonate-induced mice","volume":"15","author":"Wang","year":"2008","journal-title":"Phytomedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/j.jtcme.2025.06.003","article-title":"Cinnamaldehyde inhibits the NLRP3 inflammasome and inflammatory response by reducing oxidative stress in Neisseria gonorrhoeae-infected macrophages","volume":"16","author":"Hua","year":"2026","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"106570","DOI":"10.1016\/j.intimp.2020.106570","article-title":"Cinnamaldehyde suppresses NLRP3 derived IL-1\u03b2 via activating succinate\/HIF-1 in rheumatoid arthritis rats","volume":"84","author":"Liu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107381","DOI":"10.1016\/j.bioorg.2024.107381","article-title":"Discovery of digallic acid as XOD\/URAT1 dual target inhibitor for the treatment of hyperuricemia","volume":"147","author":"Zheng","year":"2024","journal-title":"Bioorg Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111932","DOI":"10.1016\/j.intimp.2024.111932","article-title":"Signaling pathways in uric acid homeostasis and gout: From pathogenesis to therapeutic interventions","volume":"132","author":"Yang","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"157115","DOI":"10.1016\/j.phymed.2025.157115","article-title":"Puerarin-rich compound Puerariae lobatae formulas alleviate hyperuricemia in mice by enhancing renal and intestinal function through regulating gut microbiota","volume":"146","author":"Li","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"120185","DOI":"10.1016\/j.jep.2025.120185","article-title":"Antihyperuricemic, hepatoprotective and nephroprotective roles of Benincasae Exocarpium in hyperuricemia rats","volume":"352","author":"Tong","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103285","DOI":"10.1016\/j.fbio.2023.103285","article-title":"Cinnamon essential oil based on NLRP3 inflammasome and renal uric acid transporters for hyperuricemia","volume":"56","author":"Wang","year":"2023","journal-title":"Food Biosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"139370","DOI":"10.1016\/j.ijbiomac.2024.139370","article-title":"Anti-hyperuricemia effects of a polysaccharide-protein complex from Lentinula edodes mediated by gut-kidney axis","volume":"293","author":"Xiong","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"155800","DOI":"10.1016\/j.phymed.2024.155800","article-title":"Guizhi Shaoyao Zhimu Decoction ameliorates gouty arthritis in rats via altering gut microbiota and improving metabolic profile","volume":"131","author":"Bian","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"155813","DOI":"10.1016\/j.phymed.2024.155813","article-title":"Puerarin suppresses macrophage M1 polarization to alleviate renal inflammatory injury through antagonizing TLR4\/MyD88-mediated NF-\u03baB p65 and JNK\/FoxO1 activation","volume":"132","author":"Hu","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yang, C., Zhao, E., Zhang, H., Duan, L., Han, X., Ding, H., Cheng, Y., Wang, D., Lei, X., and Diwu, Y. (2024). Xixin Decoction\u2019s novel mechanism for alleviating Alzheimer\u2019s disease cognitive dysfunction by modulating amyloid-\u03b2 transport across the blood-brain barrier to reduce neuroinflammation. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1508726"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1111\/bju.16454","article-title":"Mitochondrial dysfunction and NLRP3 inflammasome: Key players in kidney stone formation","volume":"134","author":"Su","year":"2024","journal-title":"BJU Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.tips.2025.04.007","article-title":"Targeting the NLRP3 inflammasome for inflammatory disease therapy","volume":"46","author":"Cabral","year":"2025","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.1093\/rheumatology\/kead139","article-title":"Intestinal uric acid excretion contributes to serum uric acid decrease during acute gout attack","volume":"62","author":"Zhao","year":"2023","journal-title":"Rheumatology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Fu, Y., Chen, J., Cao, Q., Zhu, S., Chen, W., Luo, H., Zhao, Y., Bernard, L.A., Wang, X., and Tu, Q. (2025). Gut-kidney axis modulation by viable and inactivated Akkermansia muciniphila mitigates avian hyperuricemia through microbial-metabolic crosstalk. mSystems, 10.","DOI":"10.1128\/msystems.00773-25"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1016\/j.chom.2023.05.011","article-title":"Gut bacterial metabolism contributes to host global purine homeostasis","volume":"31","author":"Kasahara","year":"2023","journal-title":"Cell Host Microbe"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Liu, X., Lv, Q., Ren, H., Gao, L., Zhao, P., Yang, X., Yang, G., Xu, D., Wang, G., and Yang, W. (2020). The altered gut microbiota of high-purine-induced hyperuricemia rats and its correlation with hyperuricemia. PeerJ, 8.","DOI":"10.7717\/peerj.8664"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Frederico, M.J.S., Sulis, P.M., Pereira, L.L., Rey, D., Arag\u00f3n, M., and Silva, F. (2025). Potential Effect of Cinnamaldehyde on Insulin Resistance Is Mediated by Glucose and Lipid Homeostasis. Nutrients, 17.","DOI":"10.3390\/nu17020297"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"122559","DOI":"10.1016\/j.lfs.2024.122559","article-title":"Cinnamaldehyde\/lactulose combination therapy alleviates thioacetamide-induced hepatic encephalopathy via targeting P2X7R-mediated NLRP3 inflammasome signaling","volume":"344","year":"2024","journal-title":"Life Sci."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1261\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T14:57:44Z","timestamp":1787583464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1261"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ph19081261"],"URL":"https:\/\/doi.org\/10.3390\/ph19081261","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}