International immunopharmacology最新文献

{"title":"Plumbagin remodels the tumor immune microenvironment to overcome cisplatin resistance in tongue squamous cell carcinoma via KLF2 activation and ZWINT/NF-κB inhibition","authors":"Zichen Xu ,&nbsp;Yuqi Xin ,&nbsp;Qingkun Jiang ,&nbsp;Xinjian Zhang ,&nbsp;Yang Liu ,&nbsp;Ruiyang Zou ,&nbsp;Lizhi Zhou ,&nbsp;Danfeng Xue ,&nbsp;Jiaxuan Qiu","doi":"10.1016/j.intimp.2025.115651","DOIUrl":"10.1016/j.intimp.2025.115651","url":null,"abstract":"<div><div>Tongue squamous cell carcinoma (TSCC) is a therapeutic challenge due to frequent cisplatin resistance and an immunosuppressive tumor immune microenvironment (TIME). Effective strategies must address both barriers. We evaluated the antitumor effects of plumbagin (PLB) in cisplatin-sensitive and -resistant TSCC cells, as well as in xenograft, patient-derived xenograft, and humanized mouse models. PLB downregulated ZWINT and inhibited NF-κB signaling, thereby restoring cisplatin sensitivity in resistant cells. In vivo, PLB significantly suppressed tumor growth and enhanced cisplatin efficacy. Mechanistically, PLB stabilized KLF2, promoting JAK1/STAT2 signaling, TIME remodeling, and partial restoration of CD8⁺ T-cell function. These dual actions—tumor chemosensitization via ZWINT/NF-κB inhibition and immune reprogramming via KLF2 activation—were functionally interconnected, as cytokines released by PLB-primed T cells reinforced NF-κB suppression in tumor cells. Collectively, our findings identify PLB as a low-cost small molecule that integrates cisplatin sensitization with immune activation, offering a promising adjunctive strategy for cisplatin-refractory TSCC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115651"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cold-inducible RNA-binding protein promotes gut barrier dysfunction and visceral hypersensitivity via activating mast cells in IBS-D","authors":"Tao Wang ,&nbsp;Peiwen Yang ,&nbsp;Siyuan Dong ,&nbsp;Xin He ,&nbsp;Fei Dai ,&nbsp;Jinhai Wang ,&nbsp;Yi Lyu ,&nbsp;Rongqian Wu ,&nbsp;Jia Zhang","doi":"10.1016/j.intimp.2025.115640","DOIUrl":"10.1016/j.intimp.2025.115640","url":null,"abstract":"<div><h3>Background</h3><div>Cold-inducible RNA-binding protein (CIRP) is implicated in gut barrier function and various immune responses. Mast cells (MCs) have been found to play a key role in the pathogenesis of irritable bowel syndrome (IBS). However, the regulation of CIRP on MCs and its role in diarrhea predominant-irritable bowel syndrome (IBS-D) remains unclear.</div></div><div><h3>Methods</h3><div>CIRP expression was evaluated in IBS-D mice, which were induced via acetic acid enema in combination with restraint stress (AA/RS). To explore the direct effect of CIRP on gut barrier function, visceral sensitivity and the activity of MCs, recombinant murine CIRP protein (rmCIRP) was administered via enema for 14 consecutive days. Subsequently, a systematic CIRP knockout (CIRP^−/−) mouse was constructed successfully to further verify the role of CIRP in IBS-D.</div></div><div><h3>Results</h3><div>In present study, we found the expression of CIRP was significantly increased in IBS-D mice and corresponding cell models. Exogenous CIRP administration significantly exacerbated gut barrier dysfunction and visceral hypersensitivity, which were accompanied by the activation of MCs. Conversely, CIRP deficiency restored gut barrier function and reduced visceral sensitivity, which was associated with the inhibition of MCs activation. Further experiments revealed that C48/80, a MCs activator, eliminated the protective effect of CIRP deficiency in IBS-D mice. In addition, inhibition of TLR4 and TRPV1, respectively, eliminated the activation of CIRP on MCs.</div></div><div><h3>Conclusions</h3><div>CIRP plays a crucial role in the pathophysiology of IBS-D. Targeting CIRP may represent a promising therapeutic strategy for IBS-D.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115640"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural products inhibit inflammatory diseases by regulating macrophage polarization","authors":"Ruxuan Wang ,&nbsp;Jianfeng Gao ,&nbsp;Xinhai Jiang ,&nbsp;Wentao Yang ,&nbsp;Lianglin Wu ,&nbsp;Yulin Tian ,&nbsp;Yuehong Zheng","doi":"10.1016/j.intimp.2025.115615","DOIUrl":"10.1016/j.intimp.2025.115615","url":null,"abstract":"<div><div>Macrophages exhibit considerable adaptability. As a crucial component of the human innate immune system, macrophages can perform different functions by differentiating into different phenotypes. Macrophages undergo a constantly changing transformation, dividing into either M1 (which is the fiery type) or M2 (the calming variety) phenotypes, which drives the progression of inflammatory diseases. Given the pivotal role of macrophages in inflammation, regulating macrophage polarization may serve as a potential therapeutic target in several inflammatory diseases. Natural products, including flavonoids, terpenoids, phenols and alkaloids, have demonstrated remarkable ability to control the direction of macrophages and suppress inflammatory ailments. This is achieved by binding crucial signalling channels, such as the NF-κB, JAK/STAT, and MAPK pathways. This paper summarizes the mechanisms of macrophage polarization, highlights the therapeutic potential of natural substances, and provides valuable insights for the prevention and therapeutic management of inflammatory diseases.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115615"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil extracellular traps promote bone loss in type 1 diabetes via suppression of the FN1–PI3K/Akt signaling axis","authors":"Xin Liu ,&nbsp;Donglun Xiao ,&nbsp;Dongliang Zhang ,&nbsp;Yujun Pan ,&nbsp;Jie Guo ,&nbsp;Ying Zhang ,&nbsp;Shanshan Li ,&nbsp;Qiong Tang ,&nbsp;Xin Jin ,&nbsp;Tianwei Sun","doi":"10.1016/j.intimp.2025.115629","DOIUrl":"10.1016/j.intimp.2025.115629","url":null,"abstract":"<div><div>Diabetes-induced osteoporosis (DOP) is a severe complication of type 1 diabetes mellitus (T1D), characterized by impaired bone formation. However, the underlying mechanisms remain poorly understood. Using a streptozotocin (STZ)-induced T1D mouse model, we observed pronounced trabecular bone loss, demonstrated by micro-CT and histological analyses. Concurrently, diabetic bone marrow showed a marked accumulation of neutrophil extracellular traps (NETs), as confirmed by immunofluorescence and Western blot for MPO and citrullinated histone H3 (Cit<img>H3). Therapeutic degradation of NETs with DNase I significantly restored trabecular bone microarchitecture and enhanced osteoblast activity, evidenced by increased osteocalcin (OCN) and RUNX2 expression. In vitro, NETs impaired osteogenic differentiation of MC3T3-E1 cells, suppressing ALP activity and downregulating osteogenic markers OPN and RUNX2—effects that were reversed by DNase I. Transcriptomic profiling revealed that NETs downregulated fibronectin 1 (FN1), disrupting PI3K/Akt signaling and ECM-receptor interaction pathways. Restoration of FN1 expression, either in vivo via DNase I or in vitro via exogenous supplementation, rescued osteogenic capacity. Furthermore, inhibition of PI3K signaling with LY294002 abrogated the osteoprotective effects of FN1, confirming that the FN1–PI3K/Akt axis mediates NETs-induced osteogenic suppression. These findings identify NETs as critical mediators of diabetic bone loss through FN1 downregulation and suppression of PI3K/Akt signaling. Targeting NETs or restoring FN1–PI3K/Akt signaling may therefore represent promising therapeutic strategies for diabetes-associated osteoporosis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115629"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145244554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigation of galangin against colorectal cancer through MAPK signaling pathway modulation","authors":"Yingzi Wu ,&nbsp;Jinhai Luo ,&nbsp;Baojun Xu","doi":"10.1016/j.intimp.2025.115636","DOIUrl":"10.1016/j.intimp.2025.115636","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is a major global health burden with poor prognosis due to high metastasis and recurrence rates. Galangal has shown potential anti-cancer effects, but its mechanisms remain unclear. This study aims to dig out the anti-CRC effects of galangal and its potential mechanisms. Network pharmacology was used to explore the bioactive compounds and predict potential targets and pathways of galangal against CRC. Additionally, we employed a wide range of assays to identify the impact of the bioactive compound of galangal on the biological function of CRC cells <em>in vitro</em>, including CCK-8, EdU staining, colony formation, wound healing, transwell assay and Western blot analysis. Through network pharmacology analysis, we identified galangin as the bioactive compound of galangal. Galangin significantly inhibited the proliferation and migration of CRC cells <em>in vitro</em> with low toxicity. It arrested cell cycle at the G0/G1 phase and promoted apoptosis by increasing reactive oxygen species (ROS) levels and decreasing mitochondrial membrane potential. RNA sequencing revealed that galangin modulated the MAPK signaling pathway, which was further confirmed by Western blot analysis showing inhibition of MAPK activation. Importantly, MAPK signaling pathway activator was used to further verified that galangin inhibited HCT15 cells proliferation by suppressing MAPK signaling pathway. Our research suggested that galangin, which is the bioactive compound of galangal, demonstrates potent inhibitory effects on CRC cell proliferation and metastasis by modulating the MAPK signaling pathway. Our findings suggest that galangin is a promising candidate for CRC therapeutics, warranting further investigation for <em>in vivo</em> even clinical application.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115636"},"PeriodicalIF":4.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting TBXAS1: a novel target of daidzein in alleviating APAP-induced hepatic injury","authors":"Lei Sun ,&nbsp;Ziming Wu ,&nbsp;Zhiwei Huang ,&nbsp;Han Li ,&nbsp;Pengru Wang ,&nbsp;Jiatong Chen ,&nbsp;Boyuan Gu ,&nbsp;Shenglu Liu ,&nbsp;Yu Jiang ,&nbsp;Xiaolin Zhong ,&nbsp;Yichao Du ,&nbsp;Wenguang Fu","doi":"10.1016/j.intimp.2025.115633","DOIUrl":"10.1016/j.intimp.2025.115633","url":null,"abstract":"<div><h3>Background and Purpose</h3><div>Acetaminophen (APAP) overdose is a major cause of acute liver failure. TBXAS1, driving inflammation via processes like inflammatory cell aggregation, vasoconstriction, and thrombosis, was picked out as a crucial inflammatory regulator that catalyzes thromboxane A2 generation. This study was conducted to explore whether Daidzein (DAI), a bioactive compound, has hepatoprotective effects against APAP-induced liver injury by acting on TBXAS1.</div></div><div><h3>Methods and Results</h3><div>In vitro and in vivo experiments revealed that hepatic TBXAS1 levels increased following APAP induction. SiRNA-mediated TBXAS1 knockdown reduced APAP-induced inflammation and cytotoxicity. Network pharmacology and transcriptomic analysis identified TBXAS1 as a potential DAI target. In vivo, DAI pretreatment mitigated APAP-induced liver injury in mice and lowered TBXAS1 levels. In vitro, DAI pretreatment followed by APAP exposure in AML-12 cells resulted in reduced TBXAS1 expression and decreased inflammation, oxidative stress, and apoptosis. Mechanistic analysis showed that DAI regulates TBXAS1 expression both in vitro and in vivo. Specifically, DAI modulates the TLR4/NF-κB pathway by altering TXA2 levels mediated by TBXAS1, thereby protecting against APAP-induced injury.</div></div><div><h3>Conclusion</h3><div>TBXAS1 is identified as a novel target of DAI. By modulating TBXAS1, DAI can reduce APAP-induced liver damage, including hepatocyte injury, oxidative stress, apoptosis, and inflammation. This study provides a new therapeutic approach for managing APAP-induced liver damage.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115633"},"PeriodicalIF":4.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pregnane X receptor activation attenuates intestinal inflammation: The role of pyroptosis and necroptosis inhibition","authors":"Yuwei Zheng ,&nbsp;Chunyu Qiao ,&nbsp;Wanzhe Xiao ,&nbsp;Bingxue Liu ,&nbsp;Wenyuan Long ,&nbsp;Jiexing Zhang ,&nbsp;Shuai Lian ,&nbsp;Xuming Deng ,&nbsp;Hongming Lv","doi":"10.1016/j.intimp.2025.115620","DOIUrl":"10.1016/j.intimp.2025.115620","url":null,"abstract":"<div><div>Intestinal inflammation compromises epithelial barrier integrity and disrupts immunological homeostasis, escalating the risk of severe gastrointestinal disorders. The Pregnane X Receptor (PXR), a xenobiotic-sensing nuclear receptor, is critical for maintaining intestinal structural integrity and suppressing inflammation, although its mechanistic underpinnings remain poorly characterized. In this study, we explored the therapeutic potential of PCN, a PXR agonist, in mitigating intestinal inflammation using two models: enterohaemorrhagic <em>Escherichia coli</em> O157:H7 (EHEC)-infected mice and lipopolysaccharide (LPS)-stimulated intestinal epithelial cells. PCN administration significantly improved survival rates in EHEC-challenged mice, alleviated intestinal mucosal damage, and restored tight junction protein (ZO-1 and occludin) expression. Concurrently, PCN attenuated Paneth cell dysfunction, macrophage hyperactivation, and pro-inflammatory mediator release (e.g., TNF-α, IL-6). In vitro, PCN counteracted LPS-induced barrier disruption and inflammation by suppressing the TLR4/NF-κB/MAPK axis and downstream pyroptotic (NLRP3/caspase-1/GSDMD), and necroptotic (RIPK1/RIPK3/MLKL) signaling cascades. Interestingly, both EHEC infection and LPS stimulation impaired PCN-driven PXR activation. While PCN rescued EHEC-induced mortality, histological damage, and barrier dysfunction in wild-type mice, its protective effects were markedly diminished in PXR-knockout (<em>PXR</em>^−/−) mice. Furthermore, PXR silencing in cultured cells abolished PCN-mediated inhibition of NF-κB, NLRP3 inflammasome, and necroptosis pathways. These results demonstrate that PXR activation coordinately blocks pyroptosis and necroptosis by modulating the TLR4/NF-κB/MAPK-NLRP3/caspase-1/GSDMD-RIPK1/RIPK3/MLKL axis, thereby preserving intestinal homeostasis. This dual-pathway targeting positions PXR as a promising therapeutic candidate for inflammatory bowel diseases.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115620"},"PeriodicalIF":4.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145232326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to \"Human umbilical cord mesenchymal stem cell-derived exosomes loaded miR-451a targets ATF2 to improve rheumatoid arthritis\" [Int. Immunopharmacol. 127 (2024) 111365].","authors":"Liangyu Mi, Jinfang Gao, Na Li, Ying Liu, Na Zhang, Yanan Gao, Xinyue Peng, Liyun Zhang, Ke Xu","doi":"10.1016/j.intimp.2025.115619","DOIUrl":"https://doi.org/10.1016/j.intimp.2025.115619","url":null,"abstract":"","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":" ","pages":"115619"},"PeriodicalIF":4.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chaize mixture alleviates NAFLD by regulating Glipr2-related autophagy/NLRP3 signaling","authors":"Xiaohui Zhang ,&nbsp;Juan Shi ,&nbsp;Yutong Liu ,&nbsp;Yun Lu ,&nbsp;Jing Ji ,&nbsp;Xueqian Wang ,&nbsp;Jinying Liu ,&nbsp;Fafeng Cheng ,&nbsp;Qiuxia Zhang ,&nbsp;Chongyang Ma","doi":"10.1016/j.intimp.2025.115600","DOIUrl":"10.1016/j.intimp.2025.115600","url":null,"abstract":"<div><div>Chaize Mixture (CZM), formulated by combining Xiaochaihu Decoction and Zexie Decoction, is a time-tested Chinese herbal prescription historically utilized for managing metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Despite its extensive historical use, the precise mechanisms underlying its therapeutic efficacy remain to be fully elucidated. This study aimed to delineate the molecular mechanisms of CZM in both <em>in vivo</em> and <em>in vitro</em> models of NAFLD. It was found that CZM treatment led to decreased serum ALT (alanine aminotransferase) and AST (aspartate aminotransferase), hepatic TG (triglycerides), and reduced of Srebp1, Fas, Tnf-α, IL-6, IL-1β, Tgf-β, Timp1, Timp2, Acta2, and Adamstl2, while elevating Cpt1a levels. Histopathological assessment revealed that CZM alleviated inflammatory cell infiltration, and fat accumulation in hepatocyte. CZM could increase gut microbial diversity and richness. Further multi-technique comprehensive analysis showed that Glipr2 expression was elevated in the model group but significantly decreased after CZM, which was verified by PCR and Western blotting. In addition, CZM decreased microtubule-associated protein 1 light chain 3B (LC3B), p62, NLRP3, IL-1β, Caspase1 protein levels, and increased the levels of Beclin1.</div></div><div><h3>Conclusion</h3><div>Our results showed that CZM could ameliorate steatosis, inflammatory response, and fibrosis in NAFLD by promoting autophagy and inhibiting NLRP3-mediated inflammation, which was achieved through regulating Glipr2.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115600"},"PeriodicalIF":4.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural polysaccharide PCP1 from Polygonatum cyrtonema Hua attenuates atherosclerosis via dual-target suppression of CD36/MSR1 and TLR4/NF-κB pathways","authors":"Lutan Zhou ,&nbsp;Xinya Zhao ,&nbsp;Zhu Yang ,&nbsp;Chenchen Jiang ,&nbsp;Huaizheng Song ,&nbsp;Wei Liu ,&nbsp;Guodong Wang ,&nbsp;Hui Che ,&nbsp;Jun Han","doi":"10.1016/j.intimp.2025.115644","DOIUrl":"10.1016/j.intimp.2025.115644","url":null,"abstract":"<div><div>Atherosclerosis, a chronic inflammatory disease, is characterized by lipid accumulation and inflammation in arterial walls. <em>Polygonatum cyrtonema</em> Hua, a traditional Chinese medicine and functional food, has long been used to treat cardiovascular diseases. In this study, we investigated the effects of a purified polysaccharide component (PCP1) from <em>P. cyrtonema</em> Hua on atherosclerosis. <em>In vitro</em>, the influence of PCP1 on lipid accumulation and inflammation in macrophages was assessed. <em>In vivo</em>, ApoE^−/− mice fed a high-fat diet (HFD) for 12 weeks were treated with PCP1 <em>via</em> daily gavage. Subsequently, lipid levels, inflammatory markers, and atherosclerotic lesion development were evaluated. The results demonstrated that PCP1 significantly ameliorated atherosclerosis by inhibiting macrophage lipid accumulation and inflammation. Mechanistically, PCP1 downregulated CD36 and MSR1, which are involved in lipid uptake and reduced the expression of pro-inflammatory cytokines by blocking the TLR4/NF-κB signaling. Additionally, PCP1 mitigated the overactivation of aortic endothelial cells and suppressed inflammatory responses in smooth muscle cells. Overall, PCP1 uniquely exerted anti-atherosclerotic effects through dual modulation of lipid metabolism and inflammation, thereby validating its traditional use in cardiovascular conditions and highlighting its potential as a therapeutic agent.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"166 ","pages":"Article 115644"},"PeriodicalIF":4.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145217775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}