International immunopharmacology最新文献

{"title":"Ferristatin II protects nucleus pulposus against degeneration through inhibiting ferroptosis and activating HIF-1α pathway mediated mitophagy.","authors":"Cheng Su, Xingzhi Jing, Xiaoyang Liu, Yuandong Shao, Yong Zheng, Xiaodong Liu, Xingang Cui","doi":"10.1016/j.intimp.2024.113895","DOIUrl":"10.1016/j.intimp.2024.113895","url":null,"abstract":"<p><strong>Background: </strong>Nucleus pulposus (NP) degeneration represents a significant contributing factor in the pathogenesis of intervertebral disc (IVD) degeneration (IVDD), and is a key underlying mechanism in several lumbar spine pathologies. Nevertheless, the precise mechanisms that govern NP degeneration remain unclear. A significant contributing factor to IVDD has been identified as ferroptosis. Nevertheless, its function in the degeneration of NP remains uncertain. The transferrin receptor inhibitor Ferristatin II (Fer-II) has been demonstrated to possess neuroprotective properties, which are conferred by its ability to suppress ferroptosis. It is therefore crucial to investigate the mechanisms by which Fer-II exerts its protective effects against NP degradation.</p><p><strong>Methods: </strong>In order to investigate the protective effects of Fer-II, an IVDD rat model was developed by puncturing the rat tail in vivo. Human NP cells extracted with the aid of tert-butyl hydroperoxide (TBHP) and ferric ammonium citrate (FAC) interventions mimic the IVDD pathological environment in vitro.</p><p><strong>Results: </strong>The present study demonstrates that Fer-II can delay nucleus pulposus degeneration and IVDD by inhibiting ferroptosis. This conclusion was reached through epidemiological studies and in vitro and in vivo experiments. Furthermore, Fer-II was observed to alleviate oxidative stress-induced NP cell degeneration by activating the HIF-1α pathway, enhancing mitophagy, suppressing NP cell ferroptosis.</p><p><strong>Conclusions: </strong>The findings of our study indicate that Fer-II has the potential to safeguard nucleus pulposus cells from degeneration by triggering HIF-1α-mediated mitophagy. The potential of Fer-II as a promising alternative therapeutic option for the management of IVDD is worthy of further investigation.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"113895"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927232","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":"Forsythiaside A alleviates myocardial injury in streptozotocin-induced diabetes via endoplasmic reticulum stress-NLRP3 inflammasome pathway","authors":"Chuanpu Shen ,&nbsp;Qing Zhang","doi":"10.1016/j.intimp.2024.113956","DOIUrl":"10.1016/j.intimp.2024.113956","url":null,"abstract":"<div><div>The aim of this study was to evaluate for the effects of forsythiaside A (FA) on myocardial injury in streptozotocin (STZ)-induced diabetes mice. Blood glucose (BG), serum triglycerides (TG), lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), cardiac troponin (cTnI), malondialdehyde (MDA), superoxide dismutase (SOD) levels were detected in STZ mice. The structure and function of heart was observed via cardiac ultrasound. Cytokine levels in mouse serum and heart were detected using enzyme-linked immunosorbent assay (ELISA) as well as TG, LDH, CK-MB, cTnI, MDA and SOD in high glucose (Glu) induced H9c2 cells. Western blot detection of the expression of endoplasmic reticulum stress-related TXNIP/NLRP3 inflammasome pathways (GRP78, PERK, P-PERK, EIF-α, P-EIF-α, XBP1, ATF6, TXNIP and NLRP3) in SCD mice and LCG induced H9c2 cells. Endoplasmic reticulum stress activator tunicamycin (TM) was used to validate the above pathway for FA. It was also found that FA had protective effects on myocardial injury in STZ mice via restored heart function, improved cardiac pathological changes and suppressed inflammatory response as well as in Glu induced H9c2 cells. In conclusion, FA alleviated myocardial injury in diabetes via endoplasmic reticulum stress-NLRP3 inflammasome pathway.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113956"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914530","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":"Facilitating microglia M2 polarization alleviates p-Synephrine-induced depressive-like behaviours in CSDS mice via the 5-HT6R-FYN-ERK1/2 pathway","authors":"Shanshan Wang ,&nbsp;Qianbin Li ,&nbsp;Di Deng ,&nbsp;Zedan Xie ,&nbsp;Kerun Cao ,&nbsp;Fan Zhang ,&nbsp;Qingying Yu ,&nbsp;Zizheng Li ,&nbsp;Yuantian Ma ,&nbsp;Shasha Bai ,&nbsp;Jinlan Zhao ,&nbsp;Lei Yang ,&nbsp;Qi Liang ,&nbsp;Lin An ,&nbsp;Rong Zhang","doi":"10.1016/j.intimp.2024.113926","DOIUrl":"10.1016/j.intimp.2024.113926","url":null,"abstract":"<div><div>In recent years, modulation of microglial phenotype transformation has emerged as a promising strategy for treating central nervous system disorders. <em>Aurantii Fructus Immaturus</em> (Zhishi), a traditional Chinese medicine with versatile applications, contains p-Synephrine (p-SYN) as its principal bioactive compound, recognized for its anti-inflammatory efficacy. However, the molecular mechanisms underlying these effects remain unclear. This study aimed to elucidate the mechanisms through which p-SYN modulates the microglial phenotype and alleviates neuroinflammation using both a chronic social defeat stress (CSDS) model and a lipopolysaccharide-induced human microglial cell (HMC-3) system. The antidepressant effects of p-SYN were assessed using various behavioural tests including social interaction, three-chambered social interaction, sucrose preference, tail suspension, forced swimming, open field, and novelty-suppressed feeding tests. Additionally, brain penetration of p-SYN was determined using LC-MS. The results indicated that p-SYN mitigated CSDS-induced social deficits and depressive-like behaviours, and lowered inflammatory responses, as evidenced by decreased levels of TNF-α and IL-6 and increased IL-10 levels. Moreover, p-SYN reduced the expression of M1 markers CD86 and iNOS, while increasing that of M2 markers Arg-1 and CD206. Cellular thermal shift assay, drug affinity reaction target stabilization technology, and co-immunoprecipitation demonstrated that p-SYN directly binds to the 5-hydroxytryptamine 6 receptor (5-HT6R), leading to weakening 5-HT6R and tyrosine kinase FYN interaction and inhibiting the 5-HT6R-FYN-ERK1/2 pathway. This enhances the production of anti-inflammatory factors, subsequently shifts microglia to the M2 phenotype, and eventually mitigates neuroinflammation, thereby exhibiting antidepressant properties.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113926"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CREG1 attenuates intervertebral disc degeneration by alleviating nucleus pulposus cell pyroptosis via the PINK1/Parkin-related mitophagy pathway","authors":"Yang Zhang ,&nbsp;Deguo Xing ,&nbsp;Yi Liu ,&nbsp;Shiyu Sha ,&nbsp;Yueying Xiao ,&nbsp;Zhonghao Liu ,&nbsp;Qingfeng Yin ,&nbsp;Zengxin Gao ,&nbsp;Wenguang Liu","doi":"10.1016/j.intimp.2024.113974","DOIUrl":"10.1016/j.intimp.2024.113974","url":null,"abstract":"<div><div>Intervertebral disc degeneration (IVDD) is a chronic degenerative disease with a complex pathophysiological mechanism. Increasing evidence suggests that the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis of nucleus pulposus cells (NPCs) plays a crucial role in the pathological progression of IVDD. Pyroptosis is a novel form of programmed cell death characterized by the formation of plasma membrane pores by gasdermin family proteins, leading to cell swelling, membrane rupture, and the release of inflammatory cytokines, which trigger an inflammatory response. The close relationship between pyroptosis and mitophagy has been previously described in various diseases, but the crosstalk between pyroptosis and mitophagy in IVDD remains unexplored. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and homeostasis regulation and has been shown to promote lysosomal biogenesis and function. However, the potential role and underlying mechanisms of CREG1 in the progression of IVDD have not yet been reported. In this study, we first observed that CREG1 is downregulated following IVDD and that pyroptosis occurs. Furthermore, CREG1 knockdown inhibited NPC proliferation and exacerbated apoptosis and degeneration. Moreover, we confirmed that CREG1 knockdown induced NLRP3 activation while also leading to mitophagy inhibition and mitochondrial dysfunction in NPCs. CREG1 overexpression ameliorated LPS-induced mitophagy inhibition and mitochondrial dysfunction by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. However, these protective effects were reversed by pretreatment with the mitophagy inhibitor cyclosporin A (CsA). In a rat model of IVDD, imaging and histological assessments revealed that CREG1 overexpression effectively alleviated the progression of IVDD. Additionally, CREG1 overexpression reduced the expression of NLRP3, caspase-1, and IL-1β while increasing the expression of collagen II, PINK1 and LC3, delaying the course of IVDD. Overall, this study highlights the importance of the interplay between CREG1-mediated regulation of mitophagy and pyroptosis in the pathogenesis of IVDD, identifying CREG1 as a promising therapeutic target for IVDD treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113974"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921681","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":"OTUD4-mediated inhibition of YAP1 signaling pathway in ovarian cancer: Implications for macrophage polarization and recruitment","authors":"Mingyue Li ,&nbsp;Yanpeng Tian ,&nbsp;Lulu Si ,&nbsp;Hanlin Fu ,&nbsp;Tianjiao Lai ,&nbsp;Ruixia Guo","doi":"10.1016/j.intimp.2024.114011","DOIUrl":"10.1016/j.intimp.2024.114011","url":null,"abstract":"<div><div>Ovarian cancer is a malignancy gynecologic oncology with high incidence and high mortality rate. M2-like tumor-associated macrophages promote cancer cell migration and metastasis. Ovarian tumor family deubiquitinase 4 (OTUD4) belongs to deubiquitinating enzyme family. The roles of OTUD4 in tumor microenvironments in ovarian cancer remains unknow. In this work, OTUD4 was overexpressed or knocked down in high-grade serous ovarian cancer cells OVCAR8 and CAOV3. Ovarian cells were co-cultured with THP-1 macrophages to simulate the tumor microenvironment. We found that OTUD4-expressed ovarian cells inhibited macrophage chemotaxis and M2 polarization. Besides, in ovarian tumor–bearing mouse model, OTUD4 suppressed tumor metastasis and remodeling tumor-associated macrophages phenotype (pro-tumor M2 to anti-tumor M1). In mechanism, OTUD4 protein bound to YAP1 protein, and downregulation of OTUD4 enhanced K63 ubiquitination and nuclear translocation of YAP1, thus increasing CCL2 transcription and subsequent macrophage recruitment. OTUD4 might inhibit CCL2 expression to regulate tumor-associated macrophages in ovarian tumor microenvironment. Those findings present a potential therapeutic strategy for ovarian cancer.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114011"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948315","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":"Beclin1 regulates yak endometrial inflammation and TLR4/NF-κB signaling pathway through autophagy/non-autophagy function","authors":"Wenbin Ma ,&nbsp;Libin Wang ,&nbsp;Yangyang Pan ,&nbsp;Meng Wang ,&nbsp;Jinglei Wang ,&nbsp;Min Feng ,&nbsp;Junqian Wang ,&nbsp;Hui Zhang ,&nbsp;Rui Zhang ,&nbsp;Zhengxing Jiao ,&nbsp;Yan Cui ,&nbsp;Sijiu Yu","doi":"10.1016/j.intimp.2024.113940","DOIUrl":"10.1016/j.intimp.2024.113940","url":null,"abstract":"<div><div>Beclin1 is an autophagy related factor, and it is capable of mediating non-autophagy functions, too. Yak endometritis represents a significant obstetric ailment that impedes the normal breeding process. The current understanding of the beclin1 effect on endometrial inflammation in yak remains limited. Accordingly, this study initially examined the expression profile of beclin1 in yak endometritis in vitro and vivo. Subsequently, the <em>beclin1</em> was targeted inhibit through small interfering RNA (siRNA), with the objective of elucidating the regulatory function of beclin1 in yak endometritis. The findings reveal that expression of beclin1 in inflammatory tissues of yak endometrium is markedly elevate in comparison to control group, and predominant localization in the cytoplasm of the endometrium and uterine glands. 1 µg/mL Lipopolysaccharide (LPS) was demonstrated to induce yak endometrial epithelial cells (YEECs) inflammation and increase the expression of beclin1. YEECs are disposed with 1 μg/mL LPS, resulting in a gradual increase of p62 expression from 0 h to 6 h, and significant decrease at 12 h, at 9 h to 12 h the expression of LC3 significant increase. These findings indicate that LPS impairs autophagy during the initial stages of inflammation, complete autophagy is occurred in cells during the subsequent phase. Initial stages of inflammation, inhibit <em>beclin1</em> result significantly reduced expression of inflammatory factors (TNF-α and IL-1β) and TLR4/NF-κB signaling pathway (p65, IκBα phosphorylation, p65 nuclear translocation) compared to the control group. When complete autophagy occurred, inhibit <em>beclin1</em> inhibit autophagy, result in a significantly higher expression of inflammatory factors (TNF-α and IL-1β) and TLR4/NF-κB signaling pathway than the control group. In conclusion, this study demonstrates for the beclin1 exerts both autophagic and non-autophagic functions during the inflammatory process in YEECs, making it become a potential target for the cure and diagnosis of various yak endometritis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113940"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052524","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":"Resveratrol alleviates blast lung injury by modulating the epithelial sodium channel (ENaC) via the PI3K/AKT pathway","authors":"Yichun Bai ,&nbsp;Chang Ma ,&nbsp;Xiaomeng Jing ,&nbsp;Jiang Wu ,&nbsp;Sanqiao Yao ,&nbsp;Linqiang Tian ,&nbsp;Xinwen Dong ,&nbsp;Zhen An ,&nbsp;Wenjie Ren","doi":"10.1016/j.intimp.2024.113995","DOIUrl":"10.1016/j.intimp.2024.113995","url":null,"abstract":"<div><div>Blast lung injury (BLI) is a major cause of death in blast injuries, largely due to pulmonary edema. Effective clearance of alveolar fluid is critical for resolving pulmonary edema, with the epithelial sodium channel (ENaC) playing a key role in this process. Resveratrol (RES), a natural compound with known antioxidant and anti-inflammatory properties, has shown promise in treating respiratory diseases. However, its potential protective effects against BLI, particularly through ENaC modulation, remain unclear. In this study, complementary <em>in vivo</em> and <em>in vitro</em> models were used to investigate mechanisms underlying pulmonary edema following a gas explosion. We discovered that RES significantly alleviated BLI by decreasing pulmonary edema, pulmonary index, W/D ratio, oxidative stress, inflammatory cell infiltration, and TNF-α and IL-1β expression levels in rat lung tissue. RES upregulated the expression of ENaC and PI3K/AKT both in rats and in A549 cells. The knockout of the <em>PI3K-p85</em> gene suppressed RES-induced upregulation of p-AKT and ENaC, reversing protein expression in A549 cells. Altogether, RES shows potential to attenuate blast-induced lung injury by upregulating <em>ENaC</em>, partly through the <em>PI3K/AKT</em> signaling pathway. This study highlights RES as a potential therapeutic agent for BLI and offers new insights into its mechanisms of action.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 113995"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970595","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":"Fibroblast growth factor 21 alleviated atopic march by inhibiting the differentiation of type 2 helper T cells","authors":"Dan Wang ,&nbsp;Yimeng Zou ,&nbsp;Tianqi Zhao ,&nbsp;Weiyue Cao ,&nbsp;Jiachi Han ,&nbsp;Qing Wu ,&nbsp;Zhitong Li ,&nbsp;Xinyu Li ,&nbsp;Peijing Liu ,&nbsp;Lin Bai ,&nbsp;Guiping Ren","doi":"10.1016/j.intimp.2025.114055","DOIUrl":"10.1016/j.intimp.2025.114055","url":null,"abstract":"<div><h3>Background</h3><div>The blood FGF21 expression has been previously suggested to increase in patients developing atopic dermatitis (AD) and asthma. However, its impact on atopic march is rarely analyzed. The present work focused on investigating the role of Fibroblast Growth Factor 21(FGF21) in atopic march mice and its underlying mechanisms.</div></div><div><h3>Methods</h3><div>The models were induced with Diisononyl phthalate (DINP) and OVA in wild-type C57BL/6 and FGF21^−/− mice. RAW264.7 cells were induced by LPS with/without FGF21 or KLB-SiRNA for in vitro analyses.</div></div><div><h3>Results</h3><div>The data indicated that there were more severe allergic reactions including IgE levels and the proportion of mast cells in the blood of FGF21^−/− mice in relative to WT model mice during the progression from AD to asthma. However, exogenous administration of FGF21 inhibited allergies. In this study, we reported that FGF21 mitigated AD-like lesions and Th1/2 or Th17/Treg cell imbalance in AD mice, and significantly decreased TSLP, IL-33, IL-4, IL-5, IL-13 and IL-17A expression on skin. During the asthma phase, FGF21 improved airway remodeling by downgrading inflammatory factors IL-4, IL-5, IL-13 and IL-17A; fibrotic markers α-SMA and Collagen I; and oxidative products MDA and ROS in wild-type model mice. Compared with WT model mice, the adverse consequences were aggravated in FGF21^−/− asthmatic mice. From the mechanistic perspective, FGF21 suppressed NF-κB/NLRP3, TGF-β1/Smad3 and JNK signaling pathways and increased Nrf2 expression in vivo and in vitro. In addition, β-Klotho knockdown attenuated the ameliorative impact of FGF21 on cellular damage. Blocking AMPKα in the LPS-treated RAW264.7 cells inhibited the reduction of FGF21 and the phosphorylation of JNK.</div></div><div><h3>Conclusions</h3><div>To conclude, FGF21 alleviated atopic march by inhibiting Th2/17 immune response, and reduced airway remodeling by regulating NF-κB/NLRP3, TGF-β1/Smad3 and AMPKα/JNK pathways. Moreover, this study provides a rationale and novel ideas for applying FGF21 in treating AD and asthma.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114055"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970786","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":"Hyaluronic acid promotes hepatocellular carcinoma proliferation by upregulating CD44 expression and enhancing glucose metabolism flux","authors":"Xiaorong Zhang ,&nbsp;Yifan Zhong ,&nbsp;Zeyu Miao ,&nbsp;Qing Yang","doi":"10.1016/j.intimp.2025.114035","DOIUrl":"10.1016/j.intimp.2025.114035","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC), known for its high malignancy, exhibits a critical feature in its progression through the alteration of metabolic pathways. Our study initially observed an increase in hyaluronic acid (HA) secretion by HCC cells through ELISA analysis. Further protein–protein interaction (PPI) network analysis highlighted CD44 and HAS2 as critical nodes, suggesting their pivotal roles in HA metabolism. Silencing of HAS2 markedly reduced HA production and suppressed cell proliferation, whereas overexpression of HAS2 enhanced HA synthesis and promoted cellular growth. Moreover, we found that HA, through binding to CD44, activates the downstream PI3K/AKT/MYC signaling pathway. This activation not only upregulates MYC expression but also leads to an increase in GLUT1 expression level. As a transcription factor for GLUT1, MYC directly facilitates its expression, thereby enhancing glucose uptake and glycolytic activity. Additionally, CD44 can directly interact with GLUT1, further promoting glucose flux. These mechanisms collectively boost anaerobic glycolysis and the hexosamine biosynthetic pathway (HBP), providing essential energy and metabolites for rapid liver cell proliferation. Our findings not only elucidate the central role of HA in regulating cellular metabolism but also lay a solid theoretical foundation for developing therapeutic strategies targeting HA-related metabolic pathways.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"Article 114035"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970788","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":"Hedyotis diffusa injection modulates the ferroptosis in bladder cancer via CAV1/JUN/VEGFA.","authors":"Kaiping Bai, Yanxi Long, Fei Yuan, Xiaoling Huang, Pengtao Liu, Yanping Hou, Xiangyu Zou, Tao Jiang, Jie Sun","doi":"10.1016/j.intimp.2024.113925","DOIUrl":"https://doi.org/10.1016/j.intimp.2024.113925","url":null,"abstract":"<p><p>Hedyotis diffusa Willd. (HDW), a traditional Chinese medicinal plant, exhibits a variety of pharmacological effects and has anticancer potential for a wide range of cancer types; Ferroptosis is a non-apoptosis-regulated cell death induced by iron accumulation and subsequent lipid peroxidation; and there is currently an increasing interest in the therapeutic role of ferroptosis in cancer. However, the effects of HDW on bladder cancer and its underlying molecular mechanisms remain largely unknown. In this study, a combination of in vivo and in vitro experiments, network pharmacology and data mining methods were used to investigate the effects of HDW on BLCA. The results showed that HDW exerted its anticancer activity by inducing ferroptosis in bladder cancer cells. Subsequently, we demonstrated for the first time that HDW induced ferroptosis in vitro and in vivo. To further explore the possible targets of HDW-induced ferroptosis in bladder cancer, we performed network pharmacological analyses, transcriptomic analyses, and single-cell analyses; through integrative analyses, we identified three key pivotal genes associated with iron death, CAV1, VEGFA, and JUN.Mechanistically, we showed that CAV1, VEGFA and JUN are key determinants of HDW-induced ferroptosis in BLCA. Knockdown of target genes altered the anticancer effects of HDW in 5637 and T24 cells. In conclusion, our data show for the first time that HDW exerts its anticancer effects on BLCA through CAV1, VEGFA and JUN gene-induced ferroptosis. This is expected to provide a promising compound for bladder cancer therapy.</p>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"147 ","pages":"113925"},"PeriodicalIF":4.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052232","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}