European journal of pharmacology最新文献

{"title":"Endoplasmic reticulum stress modulation by Alpha-Pinene in a rotenone-induced rat model of Parkinson's disease","authors":"B. Tezcan Yavuz ,&nbsp;E. Kabartan Cokeli ,&nbsp;G. Hacioglu ,&nbsp;S. Cirrik ,&nbsp;C. Sirin Tomruk ,&nbsp;C. Tomruk","doi":"10.1016/j.ejphar.2025.178125","DOIUrl":"10.1016/j.ejphar.2025.178125","url":null,"abstract":"<div><div>Age is the most significant risk factor for Parkinson's disease, a common and progressive neurodegenerative disorder; however, exposure to toxic substances is also strongly implicated. Rotenone, an organic pesticide, induces neuropathological features of Parkinson's disease, and is widely used to create rodent models of the condition. Although the molecular mechanisms involved in the onset and progression of the disease are still unknown, neurodegenerative diseases due to protein accumulation in certain areas of the brain, have been associated with endoplasmic reticulum stress. Therefore, preventing or mitigating endoplasmic reticulum stress is considered a promising strategy for alleviating symptoms or slowing the progression of such diseases. In this study, the endoplasmic reticulum stress-related effect of Alpha Pinene, a herbal component, was investigated for the first time in a Rotenone-induced rat model of Parkinson's disease. 60 adult male rats were divided into 5 groups as Control, Vehicle, Rotenone (2 mg/kg), Alpha Pinene (50 mg/kg) and Alpha Pinene + Rotenone. After 28 days of experimental period, it was found that Alpha Pinen maintained the body weight of rats and prevented the deterioration of motor behaviours. Histological and immunohistochemical examinations of brain tissue revealed that it protected dopaminergic neurons and glial cells in the substantia nigra. Additionally, according to the biochemical analyses in the prefrontal cortex and mesencephalon regions of the brain, it was found that Alpha Pinene inhibited apoptosis and reduced endoplasmic reticulum stress. The results indicate that Alpha Pinene is a valuable compound for Parkinson's disease with its versatile neuroprotective effect.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1005 ","pages":"Article 178125"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145010118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpinetin protects against myocardial ischemia–reperfusion injury by inhibiting ferroptosis and apoptosis via mitochondrial ferritin","authors":"Chenchao Zou ,&nbsp;Fajia Hu ,&nbsp;Xiuqi Wang ,&nbsp;Lanxiang Liu ,&nbsp;Huaxi Zou ,&nbsp;Jichun Liu ,&nbsp;Songqing Lai ,&nbsp;Huang Huang","doi":"10.1016/j.ejphar.2025.178123","DOIUrl":"10.1016/j.ejphar.2025.178123","url":null,"abstract":"<div><h3>Purpose</h3><div>Ischemia–reperfusion injury remains a major problem following myocardial infarction. Alpinetin (ALPT) has been reported to exhibit cardioprotective effects as well as resistance to ischemia–reperfusion injury. However, its role and mechanism during myocardial ischemia–reperfusion injury are unknown.</div></div><div><h3>Methods</h3><div>The anoxia/reoxygenation (A/R) injury model of H9c2 cells and the ischemia reperfusion (I/R) injury model of Sprague-Dawley rats were used in this study. Multiple indicator evaluations, flow cytometry, western blot, and transmission electron microscopy were performed to assess the protective effect of alpinetin pretreatment and its mechanism of action. In addition, the role of mitochondrial ferritin (FTMT) in alpinetin-based protection was investigated using pAD/FTMT-shRNA. The experimental findings were ultimately validated in rat I/R injury models.</div></div><div><h3>Results</h3><div>Similar to ferrostatin-1, alpinetin decreased prostaglandin-endoperoxide synthase 2 (PTGS2), lactate dehydrogenase, malondialdehyde, ferrous iron, reactive oxygen species, and oxidized glutathione disulfide (GSSG) levels and increased cell viability, glutathione (GSH) levels, the GSH/GSSG ratio, and glutathione peroxidase 4 protein levels in the injury models. Alpinetin also reversed A/R injury-induced increased caspase-3 activity and apoptosis rate and decreased Bcl-2/Bax ratio and mitochondrial membrane potential level. Of note, alpinetin attenuated mitochondrial damage induced by A/R injury. These protective effects were blocked via FTMT silencing.</div></div><div><h3>Conclusion</h3><div>Alpinetin protects against myocardial ischemia–reperfusion injury by inhibiting ferroptosis and apoptosis via FTMT.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1005 ","pages":"Article 178123"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the KRAS-p38-ATF4 axis enhances the therapeutic sensitivity of the peptide PDBAG1 in ovarian cancer via stress response modulation","authors":"Yue Wu ,&nbsp;Xingxing Li ,&nbsp;Yayi Hou ,&nbsp;Mingming Lv ,&nbsp;Shuli Zhao","doi":"10.1016/j.ejphar.2025.178128","DOIUrl":"10.1016/j.ejphar.2025.178128","url":null,"abstract":"<div><div>We previously screened a peptide PDBAG1 that remarkably inhibited triple-negative breast cancer, and found that its target was C1QBP. Recently, C1QBP has been reported as a potential tumor marker in ovarian cancer, which of the mortality rate ranks first among malignant tumors of the female reproductive tract. However, it is unclear whether and how PDBAG1 plays a regulatory role in ovarian cancer. Here, we first found that PDBAG1 definitely inhibited the growth and metastasis of ovarian cancer in vitro and in vivo. PDBAG1 downregulated the protein level of C1QBP and damaged mitochondria in ovarian cancer. Furthermore, we analyzed the overall impact of PDBAG1 on ovarian cancer cells through transcriptomics, and found that KRAS, inflammation and stress-related signals were dramatically activated. The accuracy of the transcriptome sequencing results was also subsequently verified. Moreover, we combined the inhibitors of the classic downstream MAPK signaling pathway of KRAS and the integrated stress inhibitor with PDBAG1, and found that the p38 MAPK inhibitor, Adezmapimod, significantly enhanced the inhibitory effect of PDBAG1 on ovarian cancer and inhibited the upregulation of the crucial stress response transcription factor ATF4 caused by PDBAG1. Collectively, our research results revealed the function and mechanism of the peptide PDBAG1 in ovarian cancer, providing new insights into clinical drug development for ovarian cancer.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178128"},"PeriodicalIF":4.7,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanomedicine solutions for inhibiting anastasis and inducing apoptosis to mitigate relapse in treatment-resistant cancers","authors":"Seyyed Reza Hashemi ,&nbsp;Fatemeh Hosseinpour-Soleimani ,&nbsp;Mehdi Abedi ,&nbsp;Amir Tajbakhsh ,&nbsp;Mohammad Mehdi Nemati ,&nbsp;Zahra Salmasi ,&nbsp;Amir Savardashtaki ,&nbsp;Cambyz Irajie","doi":"10.1016/j.ejphar.2025.178121","DOIUrl":"10.1016/j.ejphar.2025.178121","url":null,"abstract":"<div><div>Cancer is a leading cause of global mortality, significantly impacted by treatment resistance and the toxicity of conventional therapies like chemotherapy and radiation. Recent studies show that anastasis—the recovery of cells from near-death states—as a key mechanism promoting cancer relapse and apoptosis resistance. During anastasis, stress-induced caspase activation allows cancer cells to survive, increase chemoresistance, and enhance metastatic potential. Heat shock proteins (HSPs) reinforce this resilience by repairing damaged proteins and maintaining cell viability under stress. This review presents novel nanotechnology-based strategies that disrupt these survival pathways by targeting HSP inhibitors and caspase modulators directly to tumors using advanced nanoparticles. By focusing on the interplay between anastasis and apoptosis, our approach aims to inhibit the mechanisms that enable cancer cells to evade death while enhancing treatment delivery precision and minimizing systemic toxicity. These nanotech-enhanced strategies promise to overcome treatment resistance and lead to safer, more effective anticancer therapies. Such innovations could significantly advance our understanding of cell death and survival in cancer, paving the way for next-generation therapeutic interventions.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178121"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E2027 (irsenontrine), a phosphodiesterase 9 inhibitor, enhances cholinergic function when combined with donepezil hydrochloride","authors":"Mai Ando ,&nbsp;Kazuto Yamazaki ,&nbsp;Eri Takahashi ,&nbsp;Sadaharu Kotani ,&nbsp;Toshal Patel ,&nbsp;Andrea Bradford ,&nbsp;Jane Gartlon ,&nbsp;Yoshihiko Norimine ,&nbsp;Kanta Horie","doi":"10.1016/j.ejphar.2025.178126","DOIUrl":"10.1016/j.ejphar.2025.178126","url":null,"abstract":"<div><div>Phosphodiesterase 9 (PDE9) is an enzyme that hydrolyzes cyclic guanosine monophosphate (cGMP)—a second messenger that regulates neuronal plasticity and memory function. PDE9 inhibition has been shown to enhance cognitive function in rodents, underlining the potential of PDE9 inhibitors (PDE9Is) as novel therapeutics for cognitive dysfunction. Considering the critical role of nitric oxide (NO)-cGMP signaling cascade in acetylcholine (ACh) release, the combination of PDE9Is and acetylcholinesterase inhibitors may synergistically elevate ACh levels in the brain. In this study, we investigated the combined effects of a potent and selective PDE9I—E2027 (irsenontrine)—and donepezil hydrochloride using rat cognition impairment models and human induced pluripotent stem cell (iPSC)-derived cholinergic neurons. In rat models of natural forgetting and scopolamine-induced memory impairment, co-administration of E2027 and donepezil hydrochloride at sub-efficacious doses significantly improved the novel object discrimination index compared to monotherapy with donepezil hydrochloride. Moreover, we detected a significant increase in hippocampal ACh levels in rats treated with the combination. In human iPSC-derived cholinergic neurons, E2027 increased both intracellular cGMP and extracellular ACh levels in a concentration-dependent manner. The combination of E2027 and donepezil hydrochloride synergistically elevated extracellular ACh levels in the human cholinergic neurons model. These findings suggest a potential therapeutic mechanism for E2027 and donepezil hydrochloride combination therapy for dementia.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178126"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of indoleamine 2,3-dioxygenase by 1-methyl-D-tryptophan (1-MT) rescued PTSD-like symptoms via downregulation of neuroinflammation and NMDA receptor","authors":"Patel Parthkumar Rakeshkumar ,&nbsp;Krushna Chandra Maharana ,&nbsp;Sumadhura Bommaraju ,&nbsp;Mrunali D. Dhokne ,&nbsp;Ashok Kumar Datusalia","doi":"10.1016/j.ejphar.2025.178122","DOIUrl":"10.1016/j.ejphar.2025.178122","url":null,"abstract":"<div><div>Post-traumatic stress disorder (PTSD) is a debilitating mental health condition stemming from exposure to traumatic events. Current treatment for PTSD is limited to the selective serotonin reuptake inhibitors, which are often associated with severe side effects and result in poor treatment adherence and limited effectiveness. Recent studies indicate that indoleamine 2,3-dioxygenase (IDO) may play a significant role in the development of stress-related disorders. As a result, targeting and inhibiting IDO could offer a promising new approach for treating conditions like PTSD. Therefore, 1-Methyl-D-tryptophan (1-MT), an IDO inhibitor, was tested in rats exhibiting PTSD-like symptoms. The rat model for PTSD was created using foot shock stress (FSS) as a method to simulate traumatic experiences. Following the induction of PTSD, the potential benefits of 1-MT were assessed by performing a series of tests, including sucrose preference, freezing behaviour, light-dark transition, and open field tests. Additionally, biochemical evaluation, ELISA, western blotting, and immunohistochemistry were utilized to investigate the pharmacological effects of 1-MT. 1-MT significantly reduced PTSD symptoms, as shown by improvements in behavioural parameters, cortisol levels, and oxidative stress markers, specifically GSH and MDA. 1-MT effectively treated the expression levels of IDO, TNF-α, and the phosphorylation of NF-κB in both the hippocampus and the PFC. By inhibiting IDO and reducing neuroinflammation, it further lessened the overexpression of N-Methyl-D-Aspartate (NMDA) receptor subunit NR1. Overall findings strongly suggest that 1-MT could serve as a potential therapeutic agent to treat PTSD by alleviating the TNF-α/NF-κB/IDO signaling pathway.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178122"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integration of transcriptomics and metabolomics to reveal crizotinib-induced liver injury in mice","authors":"Haoyang Chen ,&nbsp;Huihui Liu ,&nbsp;Jingyao Wei ,&nbsp;Ruijuan Liu ,&nbsp;Xin Tian","doi":"10.1016/j.ejphar.2025.178096","DOIUrl":"10.1016/j.ejphar.2025.178096","url":null,"abstract":"<div><div>Drug-induced liver injury is a major cause of acute liver failure. Crizotinib is a first-line treatment for patients with cellular-mesenchymal epithelial transition factor (c-MET), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1)-positive non-small cell lung cancer. Although some patients treated with crizotinib experience hepatic adverse effects, the underlying mechanisms remain unclear. In this study, we integrated transcriptomic and metabolomic approaches to understand the molecular mechanisms of crizotinib-induced liver injury. After administering 500 mg/kg of crizotinib via gavage for two consecutive days, we observed elevated transaminase levels in mouse plasma, accompanied by increased hepatic lipid peroxidation and cell death. Multi-omics analysis revealed that crizotinib induces ferroptosis through processes such as cholesterol metabolism, glutathione metabolism, oxidative phosphorylation, and iron ion transport. Notably, changes in RNA methylation levels may play a crucial role in the ferroptosis triggered by crizotinib. Our findings highlight ferroptosis as an important mechanism underlying crizotinib-induced liver injury, providing new insights into the adverse drug reaction mechanisms of crizotinib.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178096"},"PeriodicalIF":4.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KPNA2 expression as a biomarker for immunosuppressive microenvironment predicting response to TKI and immunotherapy in metastatic renal cell carcinoma","authors":"Xianglai Xu ,&nbsp;Xin Xie ,&nbsp;Jiajun Wang ,&nbsp;Tianxiang Chen ,&nbsp;Yanjun Zhu","doi":"10.1016/j.ejphar.2025.178120","DOIUrl":"10.1016/j.ejphar.2025.178120","url":null,"abstract":"<div><h3>Background</h3><div>Immunotherapy (IO) combined with tyrosine kinase inhibitors (TKI) are now first-line therapy for advanced renal cell carcinoma (RCC), though reliable predictive biomarkers remain elusive. Recent evidence demonstrates that karyopherin α2 subunit (KPNA2), a nuclear transport regulator, plays key roles in tumorigenesis and therapy resistance.</div></div><div><h3>Methods</h3><div>Two cohorts were analyzed: an institutional cohort of metastatic RCC patients (ZS-MRCC) and the phase III JAVELIN Renal 101 trial cohort. RNA sequencing quantified KPNA2 expression in all samples. Immune infiltration and T-cell functionality were evaluated using flow cytometry and multiplex immunohistochemistry (IHC).</div></div><div><h3>Results</h3><div>Patients with low KPNA2 expression demonstrated superior objective response rates (55 % vs. 20 %) and prolonged progression-free survival (PFS) in both cohorts. Responders showed significantly decreased KPNA2 expression (P &lt; 0.05). Although, high-KPNA2 tumors exhibited increased tumor-infiltrating lymphocytes (TILs) by IHC (P &lt; 0.05) and flow cytometry (P &lt; 0.05), CD8⁺ T cells displayed functional impairment with reduced granzyme B (GZMB) expression. Elevated KPNA2 correlated positively with regulatory T cells (Tregs) and negatively with M1-like macrophages. A machine learning model incorporating KPNA2 and T-cell exhaustion markers generated a predictive score.</div></div><div><h3>Conclusions</h3><div>KPNA2 expression mediates immunosuppression and resistance to TKI + IO therapy. These findings position KPNA2 as a promising biomarker for personalizing treatment selection in advanced RCC, particularly for optimizing TKI + IO versus alternative regimens.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178120"},"PeriodicalIF":4.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antrocinol-mediated downregulation of ATG5 induces autophagy-dependent cell death and activates the unfolded protein response through PERK/CHOP signaling in lenvatinib-resistant hepatocellular carcinoma cells","authors":"Shiue-Wei Lai ,&nbsp;Yi-Chiao Cheng ,&nbsp;Ming-Shou Hsieh ,&nbsp;Kuang-Tai Kuo ,&nbsp;Vijesh Kumar Yadav ,&nbsp;Yew-Min Tzeng ,&nbsp;Chi-Tai Yeh ,&nbsp;Tung-Yao Tsai","doi":"10.1016/j.ejphar.2025.178115","DOIUrl":"10.1016/j.ejphar.2025.178115","url":null,"abstract":"<div><h3>Background</h3><div>This study seeks to provide preclinical evidence demonstrating the potential of Antrocinol, a derivative of antrocin derived from the active compound of <em>Antrodia cinnamomea</em>, as a promising small-molecule drug candidate for overcoming drug-resistant hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>We developed Lenvatinib-resistant Huh-7 and HepG₂ cell lines (Huh-7/LR, HepG2/LR) to evaluate their viability and apoptotic response to Antrocinol. Autophagy-dependent cell death was assessed in Huh-7/LR cells using Z-VAD-FMK and shATG5 transfection. Key UPR pathway markers were analyzed via Western blot and qRT-PCR. An orthotopic hepatocellular carcinoma mouse model was used to confirm Antrocinol's <em>in vivo</em> effects.</div></div><div><h3>Results</h3><div>Antrocinol reduced Huh-7/LR cell viability and increased apoptosis, with dose-dependent activation of caspase-3, -8, and -9. Z-VAD-FMK inhibited caspase activity but did not prevent apoptosis, indicating the presence of additional cell death mechanisms. Western blot and qRT-PCR confirmed UPR activation via upregulation of BiP/GRP78, PERK, eIF2α, ATF4, and CHOP. ATG5 knockdown abolished Antrocinol-induced cell death, confirming the role of autophagy. Combined with Lenvatinib, Antrocinol synergistically enhanced autophagy and apoptosis, inhibiting tumor growth <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Conclusion</h3><div>This study provides the first evidence that Antrocinol, a novel hydroxylated derivative of antrocin, synergises with Lenvatinib to exert anti-proliferative effects on Lenvatinib-resistant HCC cells. Our results indicate that Antrocinol may enhance chemosensitivity in HCC by activating the unfolded protein response (UPR) pathway, specifically through the PERK/CHOP axis, and promoting autophagy-dependent cell death. These findings suggest that autophagy acts as a tumor-suppressive mechanism in HCC, with potential therapeutic implications for overcoming drug resistance.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1006 ","pages":"Article 178115"},"PeriodicalIF":4.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MPTP controls the release of mtDNA and induces endothelial cell PANoptosis in trichloroethylene-induced immune kidney injury","authors":"Haibo Xie ,&nbsp;Jingyi Zhao ,&nbsp;Jian Chen ,&nbsp;Rui Li ,&nbsp;Hui Li ,&nbsp;Qifeng Wu ,&nbsp;Chen You ,&nbsp;Jiaxiang Zhang ,&nbsp;Bo Liang ,&nbsp;Qixing Zhu","doi":"10.1016/j.ejphar.2025.178118","DOIUrl":"10.1016/j.ejphar.2025.178118","url":null,"abstract":"<div><div>Vascular endothelial cells (ECs) damage is closely related to kidney injury. Our previous research revealed the involvement of interferon regulatory factor 1 (IRF1)-mediated PANoptosis of renal ECs in trichloroethylene (TCE)-induced immune kidney injury. However, how IRF1 regulates ECs PANoptosis remains unclear. In this study, we explored the mechanism of PANoptosis in renal ECs by introducing TCE-sensitized mice model, <em>in vitro</em> experiments and population studies. We found that serum tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) were associated with kidney and ECs injury in patients with occupational medicamentose-like dermatitis due to trichloroethylene (OMDT). The combination of TNF-α and IFN-γ influences the opening of the mitochondrial permeability transition pore (mPTP) in human umbilical vein endothelial cells (HUVECs), thereby promoting the release of mitochondrial reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). The inhibition of mPTP opening through the application of cyclosporin A (CsA) led to a decrease in the cytoplasmic release of mtDNA and a subsequent reduction in cellular PANoptosis. CsA administration not only mitigated renal damage but also inhibited PANoptosis in renal ECs and suppressed the expression of IRF1 and Z-nucleic acid-binding protein 1 (ZBP1). IRF1 suppression alleviated cellular PANoptosis, whereas concurrent ZBP1 overexpression rescued it. In summary, TNF-α combined with IFN-γ induced mitochondrial mPTP opening and facilitated mtDNA release. The presence of mtDNA enhances the intranuclear transcription of IRF1, which in turn upregulates ZBP1 expression. ZBP1 recognizes mtDNA and contributes to cellular PANoptosis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"1005 ","pages":"Article 178118"},"PeriodicalIF":4.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144987947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}