International immunopharmacology最新文献

{"title":"Research advances of PANoptosis in gastrointestinal tumors","authors":"Lin Qi ,&nbsp;Bin Lan ,&nbsp;Zhenting Zhao ,&nbsp;Yizhao Ma ,&nbsp;Jiachun Song ,&nbsp;Qingzhe Jia ,&nbsp;Pengyue Zhao ,&nbsp;Xiaohui Du","doi":"10.1016/j.intimp.2025.114931","DOIUrl":"10.1016/j.intimp.2025.114931","url":null,"abstract":"<div><div>Gastric and colorectal cancers are acknowledged as the predominant types of gastrointestinal malignancies, significantly impacting the global cancer burden. Despite advancements in basic and clinical research on gastrointestinal cancer, the pathophysiological mechanisms and developmental processes underlying these diseases remain incompletely understood. The dysregulation of programmed cell death (PCD) has been identified as a crucial factor in the progression and metastasis of malignant tumors. The effective induction of cancer cell death continues to present a major challenge in contemporary cancer research. PANoptosis, a distinctive form of PCD integrating apoptosis, pyroptosis, and necroptosis, was introduced in 2019. Upon detecting relevant stimuli, PANoptosis sensors recruit key molecules from the three death modalities through domain-specific interactions to form a PANoptosome, which executes cell death. Recent discoveries suggest that PANoptosis plays a pivotal role in the development, progression, and drug resistance of gastrointestinal cancer. Enhancing PANoptosis will provide superior control over gastrointestinal tumors through multi-pathway crosstalk and inflammatory microenvironment modulation. This review aims to serve as a comprehensive resource for researchers by exploring the molecular foundation of PANoptosis, emphasizing its importance in gastrointestinal tumor development, and addressing current challenges as well as potential future research directions in this field.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114931"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123156","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":"HRD1 regulates tumor-associated macrophage polarization through USP7 and promotes lung cancer development","authors":"Yezhou Xia,&nbsp;Xiaowu Tan,&nbsp;Saili Zeng,&nbsp;Yixia Jiang","doi":"10.1016/j.intimp.2025.114944","DOIUrl":"10.1016/j.intimp.2025.114944","url":null,"abstract":"<div><h3>Background</h3><div>Lung cancer exhibits high mortality and incidence rates, with tumor-associated macrophages (TAMs) serving as critical contributors to cancer progression.</div><div>This study investigates the unexplored mechanistic role of HRD1—an E3 ubiquitin ligase implicated in cancer — in orchestrating TAM polarization to affect lung cancer pathogenesis.</div></div><div><h3>Methods</h3><div>HRD1 expression in lung cancer using TCGA database and validated its impact <em>via</em> IHC. THP-1 cells and macrophages isolated from murine tumor tissues <em>via</em> magnetic bead sorting were transfected with the oe-HRD1 plasmid, followed by flow cytometry, ELISA, and RT-qPCR assays to investigate HRD1's regulatory effects on macrophage polarization and function. Co-IP was employed to investigate interactions between USP7 and HRD1/PD-L1, while Immunofluorescence elucidated underlying mechanisms.</div></div><div><h3>Results</h3><div>HRD1 was highly expressed in lung cancer and promotes tumor growth in tumor-bearing mice and proliferation in THP-1 cells. Strikingly, both <em>in vivo</em> and <em>in vitro</em> overexpression of HRD1 drove macrophage M2 polarization. Mechanistically, USP7 interacted independently with HRD1 and PD-L1, while HRD1 binding to USP7 facilitated PD-L1 ubiquitination. Furthermore, HRD1 overexpression upregulated USP7 expression, thereby enhancing M2 polarization.</div></div><div><h3>Conclusion</h3><div>HRD1 promotes lung cancer progression by regulating TAM M2 polarization <em>via</em> USP7, offering novel therapeutic targets and diagnostic perspectives for early-stage lung cancer intervention.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114944"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123161","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":"The natural compound PEITC ameliorates imiquimod-induced psoriasis in mice by suppressing neutrophil extracellular traps formation","authors":"Mei Bai ,&nbsp;Ning An ,&nbsp;Meng Cheng ,&nbsp;Jia Qin ,&nbsp;Jie Wang ,&nbsp;Rumeng Jia ,&nbsp;Wentao Liu ,&nbsp;Jingcai Cheng ,&nbsp;Qiang Xu ,&nbsp;Xuefeng Wu","doi":"10.1016/j.intimp.2025.114939","DOIUrl":"10.1016/j.intimp.2025.114939","url":null,"abstract":"<div><div>Neutrophil extracellular traps (NETs) play a key role in the development of psoriasis, a chronic inflammatory skin condition. We demonstrate the effects and possible mechanisms of phenethyl isothiocyanate (PEITC) in inhibiting NETs and alleviating psoriasis. In response to imiquimod (IMQ), multiple symptoms including scaly plaques and associated skin inflammations were induced in mice. IMQ additionally promotes the formation of NETs and the levels of inflammatory factors. Interestingly, a natural compound PEITC exerted an intensive activity in the treatment of psoriasis. It improved lesions and ameliorated ischemic coagulation symptoms in the dorsal skin of mice. PEITC also significantly reduced the expression of inflammatory factors in mice skin with an inhibition on NETs-related molecules, such as myeloperoxidase, neutrophil elastase and citrullinated histone H3. 16S rRNA sequencing analysis demonstrated that IMQ treatment induced significant gut microbiota dysbiosis in mice, suggesting potential detrimental effects on intestinal microbial homeostasis. However, PEITC administration did not show a statistically significant ameliorative effect on this IMQ-induced microbial imbalance. <em>In vitro</em> experiments demonstrated that PEITC significantly suppressed lipopolysaccharide (LPS)-induced NET formation, suggesting that its therapeutic effects in psoriasis may be due to the inhibition of bacterially driven neutrophil activation. Therefore, we identified PAD4, an important enzyme for post-translational modification of proteins in the production of NETs, as a new potential target of PEITC. Taken together, our findings suggest that PEITC could be a novel potential therapeutic drug to relieve psoriasis <em>via</em> the inhibition of NETs both <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114939"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123159","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":"Network pharmacology analysis reveals that coumestrol targets ZYX to inhibit ferroptosis and alleviate acute pancreatitis","authors":"Jiatong Chen ,&nbsp;Hai Xu ,&nbsp;Lin Gao ,&nbsp;Liangkun Niu ,&nbsp;Zhiwei Huang ,&nbsp;Shenglu Liu ,&nbsp;Shiyao Huang ,&nbsp;Yingjun Chen ,&nbsp;Jing Li ,&nbsp;Peng Tan ,&nbsp;Wenguang Fu","doi":"10.1016/j.intimp.2025.114948","DOIUrl":"10.1016/j.intimp.2025.114948","url":null,"abstract":"<div><h3>Aim</h3><div>The therapeutic effect of CMS on acute pancreatitis (AP) and the mechanism of targeting Zyxin (ZYX) to regulate ferroptosis in acinar cells.</div></div><div><h3>Methods</h3><div>To assess the therapeutic effects of CMS in AP, we established caerulein-induced AP and caerulein plus LPS-induced SAP mouse models. Subsequently, weighted gene co-expression network analysis (WGCNA) and network pharmacology analysis were used to investigate the mechanism and target of CMS in the treatment of AP. Molecular docking and cell biology techniques were used to explore the molecular mechanisms by which CMS mitigated ferroptosis in AP animal and cell models.</div></div><div><h3>Results</h3><div>CMS could alleviate the pathological damage of AP and SAP, inhibit ferroptosis and reduce inflammatory response. ZYX was an important target for CMS in the treatment of AP, and CMS could specifically bind to ZYX, down-regulate ZYX expression, and reduce TGF-β/SMAD pathway activity, thereby inhibiting acinar cell ferroptosis and improving pancreatic injury in AP. And we found that ZYX overexpression counteracted the inhibitory effects of CMS on TGF-β/Smad signaling and ferroptosis processes.</div></div><div><h3>Conclusion</h3><div>These results suggested that coumestrol targeting ZYX regulated the TGF-β/SMAD pathway, inhibited ferroptosis in acinar cells, and alleviated AP. Our research provided new drugs and targets for the treatment of AP.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114948"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123967","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":"miR-29a nanoparticles improve chronic insomnia by regulating microglia activation and hippocampal neuronal cell pyroptosis through PER2/NF-κB axis","authors":"Dan Hou ,&nbsp;Yujie Hu ,&nbsp;Hongxin Li ,&nbsp;Guoshuai Yang","doi":"10.1016/j.intimp.2025.114882","DOIUrl":"10.1016/j.intimp.2025.114882","url":null,"abstract":"<div><h3>Objective</h3><div>Chronic insomnia can easily lead to clinical distress or cause mental, social, physical, educational, occupational, or other functional impairments. Considering the role of circadian rhythm in insomnia, we focused on exploring the action of miR-29a in regulating the PER2 gene in improving chronic insomnia.</div></div><div><h3>Methods</h3><div>LPS induces the expression of miRNAs targeting PER2 in HMC3 and PRM cells, which was verified by RT-qPCR. Poly-lactic-<em>co</em>-glycolic acid (PLGA) nanoparticles (NP) were used to encapsulate short hairpin (sh)-miR-29a to construct sh-miR-29a-NP. Morris water environment method was employed to establish a sleep deprivation rat model to investigate the therapeutic effects of sh-miR-29a-NP. Cell viability and levels of cell polarization factors were evaluated using CCK8 and ELISA, respectively. The Morris water maze test was applied to assess the learning and memory capabilities of the rats. Immunohistochemistry, immunofluorescence, and western blot were applied to test the expression of glial cell polarization, neuronal cell activation, apoptosis, and Period2 (PER2) /nuclear factor kappa B (NF-κB) axis proteins.</div></div><div><h3>Results</h3><div>miR-29a was significantly upregulated in LPS-induced HMC3 and PRM cells, with the most significantly altered miRNAs/PER2 interaction. In LPS-induced HMC3 and PRM cells, sh-miR-29a promoted the PER2 and CD206 expressions, and inhibited the expression of ionized calcium-binding adaptor molecule 1 (IBA-1), NF-κB, and CD86, while this effect was blocked by small interfering-PER2. Further in vivo experiments confirmed that PER2 and CD206 expression was reduced, while NF-κB, CD86, and IBA-1 expression were up-regulated in the hippocampal tissue of CSD rats. However, this effect was reversed by treatment with sh-miR-29a-NP. Treatment with sh-miR-29a-NP in CSD rats shortened the escape latency and increased the number of crossings over the original platform, while inhibited the expression of NLR Family Pyrin Domain Containing 3, caspase-1, Gasdermin D (GSDMD), and TUNEL signal in the hippocampal tissue.</div></div><div><h3>Conclusion</h3><div>The regulation of PER2/NF-κB pathway by sh-miR-29a-NP promoted M2 polarization of microglial cells and inhibited neuronal cell pyroptosis, thereby improving cognitive dysfunction in chronic insomnia.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114882"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116658","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":"Prophylactic application of sodium new houttuyfonate to regulate macrophage activation and antifungal infection in intra-abdominal candidiasis model mice","authors":"Yuxin Xie ,&nbsp;Rong Wang ,&nbsp;Zhihao Wu ,&nbsp;Cheng Xie ,&nbsp;Shu Gong ,&nbsp;Jinping Zhang ,&nbsp;Hong Yu ,&nbsp;Zhangyong Song","doi":"10.1016/j.intimp.2025.114922","DOIUrl":"10.1016/j.intimp.2025.114922","url":null,"abstract":"<div><div>The abuse of immunosuppressants causes damage to the immune system, while the pathological proliferation and translocation of symbiotic <em>Candida albicans</em> can result in abdominal infection in immunocompromised people. In this study, we established a mouse peritoneal <em>C. albicans</em> infection model and investigated the effects of preventive application of Sodium New Houttuyfonate (SNH) by analyzing the proportion of immune cells, polarization of peritoneal macrophages, changes in fungal tissue load, and histology, and the data showed prophylactic SNH administration yields a double anti-infection effect in phagocytosis and regulation of immunity according to the immune inflammatory states of the body. <em>In vitro</em>, neutral red, colony counting, cytometric bead array, RT-qPCR, western blot, inhibitor treatment, and detection of reactive oxygen species (ROS) and nitric oxide (NO) production on RAW264.7 macrophages showed SNH can stimulate the production of tumor necrosis factor-alpha (TNF-α) and C<img>C motif ligand 2 (CCL2) and the release of ROS and NO through a TLR2/p38/NF-κB pathway. Taken together, our data provide an innovative insight into the prevention use of exogenous SNH for the treatment of <em>C. albicans</em> infection.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114922"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116723","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":"Diosgenin alleviates neuropathic pain based on the enhancement of autophagy and promotion of M2 polarization","authors":"Shuli Man ,&nbsp;Yaxue Zhou ,&nbsp;Xinghao Zhang ,&nbsp;Xiaoqin Tang ,&nbsp;Lu Xie ,&nbsp;Long Ma ,&nbsp;Wenyuan Gao","doi":"10.1016/j.intimp.2025.114936","DOIUrl":"10.1016/j.intimp.2025.114936","url":null,"abstract":"<div><div>Neuropathic pain has serious impacts on the quality of people's life. Diosgenin extracted from yams has shown significant potential in the treatment of nervous system diseases. To investigate the potential mechanism of diosgenin fighting against neuropathic pain, we established a chronic compression injury (CCI) model. The pain-related behaviors were determined by Von Frey, hot plate, and sciatic nerve index test. As a result, diosgenin significantly lowered the pain threshold, improved the sciatic nerve index, and decreased the damage of sciatic nerve structure in CCI model mice. It increased the protein levels of LC3-II and Beclin-1, the number of the lysosomes, decreased the protein level of P62 and the number of the autophagosomes, and therefore activated autophagy. Diosgenin also inhibited the proliferation of microglia cells and the translocation of NF-κB p65, while promoting promoted M2 polarization of microglia cells. Autophagy inhibitor like chloroquine inhibited the M2 polarization of microglia cells, and reversed the therapeutic effect of diosgenin. All in all, diosgenin alleviated neuropathic pain in CCI mice based on the enhancement of autophagy and the promotion of M2 polarization.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114936"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116657","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":"Synergistic and mechanistic effects of neogambogic acid in enhancing almonertinib sensitivity in non-small cell lung cancer","authors":"Qiqi Yang ,&nbsp;Yuan Yao ,&nbsp;Junping Wang ,&nbsp;Mengdi Pang ,&nbsp;Jinyan Wu ,&nbsp;Fusheng Yin ,&nbsp;Jun He ,&nbsp;Yanyan Wang ,&nbsp;Weidong Chen","doi":"10.1016/j.intimp.2025.114878","DOIUrl":"10.1016/j.intimp.2025.114878","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is characterized by a complex pathogenesis and high mortality. Targeted drug therapy represents a precise method of treatment. However, Improving sensitivity to targeted agents is currently a major challenge in clinical tumor therapy. Neogambogic acid (NGA), a bioactive compound isolated from the Traditional Chinese Medicine (TCM) Gamboge, has shown potential in NSCLC treatment. Nonetheless, the mechanism by which NGA enhances the sensitivity of NSCLC to the targeted drug Almonertinib remains unclear. This study aimed to elucidate the mechanisms underlying the ability of NGA to enhance the sensitivity of NSCLC to Almonertinib, revealing the synergistic effect exerted by the combination therapy. We established a subcutaneous grafted tumor model of mouse lung cancer by injecting Lewis cells, and evaluated the therapeutic efficacy <em>in vivo</em>. The study demonstrated that NGA combined with Almonertinib effectively suppressed NSCLC tumor growth by promoting cancer cell apoptosis and reducing serum tumor marker levels. <em>In vitro</em> experiments revealed that this combination synergistically inhibited lung cancer cell proliferation and induced apoptosis. Mechanistically, NGA demonstrated the ability to bind to Pregnane X receptor (PXR), regulating the expression of drug-metabolizing enzymes and transporters. We further validated this effect using PXR agonists and inhibitors in A549 cells. Additionally, the combination of NGA with Almonertinib significantly inhibited aberrant EGFR activation and downstream PI3K/AKT signaling, leading to enhanced apoptosis. This study demonstrated that the combination of NGA and Almonertinib inhibited the expression of CYP3A4, P-gp, and BCRP <em>via</em> PXR modulation. Meanwhile, it inhibited the EGFR/PI3K/AKT pathway and enhanced the sensitivity of NSCLC to Almonertinib, exerting synergistic anti-tumor effects. Our findings suggest a promising strategy for integrating active TCM components with targeted therapy in NSCLC management.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114878"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116659","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":"Isorhapontigenin suppresses inflammation, proliferation and aggressiveness of rheumatoid arthritis fibroblast-like synoviocytes by targeting farnesyl diphosphate synthase","authors":"Yingli Liu ,&nbsp;Fan Su ,&nbsp;Qian Qiu ,&nbsp;Chuyu Shen ,&nbsp;Simin Chen ,&nbsp;Wei Lin ,&nbsp;Di Liu ,&nbsp;Ruiru Li ,&nbsp;Yu Kuang ,&nbsp;Ting Liu ,&nbsp;Youjun Xiao ,&nbsp;Hao Li ,&nbsp;Hanshi Xu ,&nbsp;Liuqin Liang","doi":"10.1016/j.intimp.2025.114894","DOIUrl":"10.1016/j.intimp.2025.114894","url":null,"abstract":"<div><h3>Background</h3><div>Isorhapontigenin (ISO) has been reported to exhibit various therapeutic effects including anti-inflammation and anti-cancer. However, it is still unclear whether ISO has therapeutic efficacy on rheumatoid arthritis (RA). This study aimed to determine the effects of ISO on regulating functions of RA fibroblast-like synoviocytes (FLS) and further to explore the underlying mechanisms.</div></div><div><h3>Methods</h3><div>Cell viability was assessed by CCK8 kit, cell apoptosis was measured using Annexin V-APC/PI assay and cell proliferation was evaluated with EdU assay. The cell scratch assay, Transwell assay, and pseudopodia formation assay were applied to detect the migration and invasion of RA FLS. Proinflammatory cytokines and MMPs mRNA expression was analyzed using RT-qPCR, while protein expression was examined by western blotting assay. Furthermore, RNA sequencing was employed to identify the potential downstream targets of ISO. Collagen-induced arthritis (CIA) mice were constructed to investigate the vivo efficacy of ISO.</div></div><div><h3>Results</h3><div>ISO (12.5, 25, and 50 μΜ) showed inhibition of TNF-α-induced IL-6, IL-8, and MMP-3 expression, as well as proliferation, migration and invasion of RA FLS. However, it did not affect viability or apoptosis. Moreover, there were no significant difference in the efficacy on the proliferation, migration and invasion among ISO, methotrexate and dexamethasone. Mechanistically, farnesyl diphosphate synthase (FDPS) was identified as the novel target of ISO in RA FLS through RNA sequencing and Reactome enrichment analysis. FDPS expression was upregulated in FLS and synovial tissues from RA patients compared to healthy controls. Furthermore, both ISO treatment and FDPS knockdown were found to reduce TNF-α-induced activation of the AKT and ERK1/2 pathways. Interestingly, ISO treatment ameliorated synovial inflammation and joint destruction, and decreased synovial FDPS expression in CIA mice.</div></div><div><h3>Conclusion</h3><div>ISO treatment may attenuate the pathological behaviours of RA FLS by targeting FDPS-mediated phosphorylation of AKT and ERK1/2 pathways. Our data suggest that ISO might be a novel potential agent for RA treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114894"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123162","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":"Mitigating PCOS progression: The protective effect of C-phycocyanin on ovarian granulosa cell pyroptosis via the NRF2/NLRP3/GSDMD pathway","authors":"Jing Zhang ,&nbsp;Yaxin Chen ,&nbsp;Baoqing Han ,&nbsp;Yang Liu ,&nbsp;Xuan Li ,&nbsp;Jun Yang ,&nbsp;Yajing Liu ,&nbsp;Yunxia Cao ,&nbsp;Dan Liang ,&nbsp;Biao Yu","doi":"10.1016/j.intimp.2025.114917","DOIUrl":"10.1016/j.intimp.2025.114917","url":null,"abstract":"<div><h3>Background</h3><div>Pyroptosis is a proinflammatory cell death process that contributes to inflammatory diseases. C-Phycocyanin (C-PC) is a water-soluble protein pigment primarily derived from <em>cyanobacteria</em>, and it exhibits anti-inflammatory effects. However, the role of natural C-PC in pyroptosis in human ovarian granulosa cells (GCs), particularly in conditions like polycystic ovary syndrome (PCOS), remains unclear. This study investigates the effects of C-PC on pyroptosis and its relevance to PCOS.</div></div><div><h3>Methods</h3><div>Here dehydroepiandrosterone (DHEA) was used to induce PCOS in a mouse model that was characterized by an irregular oestrous cycle, cystic follicles and an elevated serum hormone level. DHEA treatment was used to induce GC pyroptosis. Scanning electron microscopy (SEM) was used to determine cell morphology. The expression levels of key proteins for oxidative stress and pyroptosis, including nuclear factor erythroid 2-related factor 2 (NRF2), NLR family of pyrroline-containing structural domain 3 (NLRP3) inflammasomes, cleaved caspase-1, and N-GSDMD were investigated in vivo and in vitro by Western blotting and immunofluorescence staining.</div></div><div><h3>Results</h3><div>C-PC restored the estrous cycle in PCOS mice, reduced testosterone levels, and decreased cystic follicles. It attenuated PCOS progression by reducing oxidative stress level and suppressing GCs pyroptosis. At the cellular level, C-PC inhibited DHEA-induced GC pyroptosis by blocking NLRP3 inflammasome activation and lowering ROS, effects reversed by the NRF2 inhibitor (ML385). Molecular docking analysis and CETSA suggested that C-PC may protect against PCOS by activating the NRF2 pathway or by indirectly binding to the Ser27 site of GSDMD. In addition, C-PC suppressed ROS/p38-MAPK activation induced by DHEA, and p38-MAPK agonists diminished its effect on NLRP3 inflammasome activity and GC pyroptosis protection.</div></div><div><h3>Conclusion</h3><div>C-PC exerts a protective effect on GC pyroptosis through the NRF2/NLRP3/GSDMD and ROS/p-38 MAPK pathways, highlighting its potential to mitigate inflammation and its relevance to reproductive health issues like PCOS.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114917"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123385","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}