Pharmacological research最新文献

{"title":"Curcumin modulates β-catenin stabilization via targeting proteasomal deubiquitinating enzyme USP14☆","authors":"Mengzhen Shen ,&nbsp;Lizhe Chen ,&nbsp;Jie Jiang,&nbsp;Ziye Wang,&nbsp;Qing Gong,&nbsp;Xue Zhang,&nbsp;Xisong Ke,&nbsp;Yi Qu","doi":"10.1016/j.phrs.2025.107745","DOIUrl":"10.1016/j.phrs.2025.107745","url":null,"abstract":"<div><div>Loss of β-catenin homeostasis is tightly associated with human malignancies, modulation of β-catenin stabilization could be an attractive strategy for cancer therapy. In the present study, we demonstrated that an ancient drug curcumin was associated with selective accumulation of phosphorylated β-catenin (PBC) tagged with both ubiquitin (Ub) and Ub-like (Ubl) protein NEDD8. We further identified USP14, a deubiquitinating enzyme (DUB) in 19S proteasome, as a functional target of curcumin in modulating β-catenin. Curcumin enhances USP14-mediated PBC trapping and modulates proteasome associations, loss of USP14 significantly attenuated curcumin-increased PBC. Additionally, we found that USP14 deficiency suppressed mitotic entry and cell proliferation, targeting USP14 and PBC was essential for curcumin inhibition of cancer. Taken together, our study not only revealed the association of USP14 with PBC degradation within the proteasome, but also provided a unique small molecule curcumin targeting USP14 to modulate β-catenin for cancer therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107745"},"PeriodicalIF":9.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894678","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":"Elevated activity of plasma dipeptidyl peptidase 4 upon stress can be targeted to reverse tumor immunosuppression","authors":"Peipei Li ,&nbsp;Menghe Liang ,&nbsp;Junlin Zhu ,&nbsp;Jian Chen ,&nbsp;Lin Xia ,&nbsp;Ziqi Jin ,&nbsp;Xiao Zhang ,&nbsp;Shuqing Zhang ,&nbsp;Qi Wang ,&nbsp;Zhen Liu ,&nbsp;Yu Ping ,&nbsp;Zhenxin Wang ,&nbsp;Catherine CL Wong ,&nbsp;Yi Zhang ,&nbsp;Heng Yang ,&nbsp;Zilu Ye ,&nbsp;Yuting Ma","doi":"10.1016/j.phrs.2025.107696","DOIUrl":"10.1016/j.phrs.2025.107696","url":null,"abstract":"<div><div>The interplay between stress-induced metabolic reprogramming and perturbations in the cancer-immune dialogue is a challenging research topic with huge knowledge gaps to fill. In a repeated social defeat model, we discovered that circulating corticosterone, blood glucose, and plasma DPP4 activity were increased in stressed mice. Consistently, three independent cohort studies showed that plasma DPP4 activity was positively correlated with the severity of psychological distress of newly diagnosed cancer patients. Stress-induced surge of glucocorticoid can boost DPP4 activity via glucocorticoid receptor signaling without influencing <em>Dpp4</em> transcription or the abundance of soluble DPP4. Albeit catalytic inhibition of DPP4 upon stress can’t normalize the behavioral pattern and glucocorticoid secretion, it managed to reverse the expansion of circulating neutrophils and monocytes, restored the efficacy of prophylactic tumor vaccine, and augmented the priming of tumor-antigen specific T cells. DPP4 blockade in the context of stress largely enhanced the intratumoral accumulation of CD8⁺T cells and DCs, cytokine production by CD8⁺T and NK cells in situ, and tumor antigen presentation in vitro. Proteome profiling of mouse plasma revealed stress-related DPP4-sensitive changes that can be linked to immunological alterations and disturbed protease network. Altogether, elevated DPP4 activity may be targeted in cancer patients with psychiatric comorbidities to boost anti-tumor immunity.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107696"},"PeriodicalIF":9.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873224","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":"FXR as a pivotal role linking JNK and G0s2 mitigates triptolide-induced hepatotoxicity through the regulation of metabolic disorder of liver","authors":"Qinmei Li ,&nbsp;Jianfeng Huang ,&nbsp;Qi Zhao ,&nbsp;Fei Li","doi":"10.1016/j.phrs.2025.107738","DOIUrl":"10.1016/j.phrs.2025.107738","url":null,"abstract":"<div><div>Triptolide (TP), as a principal bioactive compound derived from <em>Tripterygium wilfordii Hook. f</em>., exhibits significant anti-tumor, anti-inflammatory, and immunomodulatory properties. However, the serious adverse reactions and hepatotoxicity of TP limit its clinical application. Therefore, in this study, an intraperitoneal injection was employed to establish a TP-induced hepatotoxicity model, characterized by elevated levels of transaminases (AST and ALT) and metabolic disorders. The administration of the JNK inhibitor SP600125 effectively mitigated the elevated transaminases and inflammation induced by TP. The resistance of SP600125 to metabolic disturbances induced by TP was contingent upon <em>Fxr</em>, as demonstrated through the use of <em>Fxr</em> knockout mice. Supplementation of GW4064 restored the concentrations of bile acids, long-chain fatty acids, and carnitine disrupted by TP. Transcriptomic data suggested that <em>G0s2</em> was one of the genes most severely disrupted by TP, and the ameliorative effects of SP600125 and GW4064 were accompanied by the upregulation of <em>G0s2</em>. The expression of <em>G0s2</em> was disrupted by siRNA in vitro, thereby intensifying the cytotoxicity of TP. A comparative analysis of the impact of TP on the <em>G0s2</em> gene in two mouse models revealed that a smaller reduction in wild-type mice compared to <em>Fxr</em>^<em>-/-</em> mice, indicating that Fxr mitigates the inhibitory effect of TP on <em>G0s2</em>. The aberrant JNK/<em>Fxr</em>/<em>G0s2</em> signaling plays a key role in TP-induced hepatotoxicity. Targeting <em>Fxr</em> might be a potential strategy for alleviating the liver toxicity of TP.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107738"},"PeriodicalIF":9.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143912861","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":"Neuroprotectin D1 and GPR37 protect against chemotherapy-induced peripheral neuropathy and the transition from acute to chronic pain","authors":"Jing Xu ,&nbsp;Sangsu Bang ,&nbsp;Ouyang Chen ,&nbsp;Yize Li ,&nbsp;Aidan McGinnis ,&nbsp;Qin Zhang ,&nbsp;Ru-Rong Ji","doi":"10.1016/j.phrs.2025.107746","DOIUrl":"10.1016/j.phrs.2025.107746","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) significantly impacts patient’s quality of life and complicates cancer treatment. Neuroprotectin D1 (NPD1)/protectin D1 (PD1), derived from docosahexaenoic acid (DHA), exhibits analgesic actions in animal models of inflammatory pain and neuropathic pain. GPR37, a receptor for NPD1/PD1, is known to regulate macrophage phagocytosis and inflammatory cytokine expression, but its role in primary sensory neurons and CIPN remains poorly understood. We found <em>Gpr37</em> mRNA expression in both neurons and macrophages in mouse dorsal root ganglia (DRG), furthermore, GPR37 is downregulated by the chemotherapy agent paclitaxel. <em>Gpr37</em> mRNA was notably high in neonatal mouse DRG neurons. In contrast, <em>Gpr37l1</em> is primarily expressed by satellite glial cells in DRG. Chemotherapy-induced neuropathic pain symptom (mechanical allodynia) resolved within seven weeks in wild-type mice, but it persisted in <em>Gpr37</em> knockout mice, highlighting GPR37's role in acute-to-chronic pain transition. Consistently, intra-DRG knockdown of <em>Gpr37</em> in naive animals was sufficient to induce mechanical allodynia. In primary DRG cultures, NPD1 facilitated neurite outgrowth of sensory neurons in the presence of paclitaxel, in a GPR37-dependent manner. NPD1 treatment also mitigated mechanical allodynia and prevented the loss of intraepidermal nerve fibers in hind paw skins in wild-type mice undergoing chemotherapy, but these protective effects are absent in <em>Gpr37</em> knockout mice. Finally, spatial transcriptomics analysis revealed macrophage and neuronal expression of GPR37 in human DRG. Our findings indicate that GPR37 deficiency drives pain chronicity in CIPN. This study also underscores the potential of NPD1 in safeguarding against sensory neuron degeneration and neuropathic pain in CIPN through GPR37.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107746"},"PeriodicalIF":9.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882070","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":"Modulation of GLP-1 signalling as an innovative strategy counteracting the onset of heart failure: Potential for natural compound supplementation","authors":"Micaela Gliozzi ,&nbsp;Anna Rita Coppoletta ,&nbsp;Antonio Cardamone ,&nbsp;Cristina Carresi ,&nbsp;Rocco Mollace ,&nbsp;Vincenzo Musolino ,&nbsp;Vincenzo Mollace","doi":"10.1016/j.phrs.2025.107744","DOIUrl":"10.1016/j.phrs.2025.107744","url":null,"abstract":"<div><div>The clinical continuum of heart failure (HF) is commonly divided into four stages (A, B, C and D), but despite the identification of its staging, to date, the management of the early phases remains an unmet need. In fact, the incomplete knowledge of the molecular mechanisms associated with the comorbidities leading to HF onset represents an obstacle to a targeted therapy. Recently, stages A and B have been further typified and, starting from this novel characterization, the aim of our review was to propose an alternative criterion to appropriately use GLP-1 RA in association with plant-derived polyphenolic extracts. This alternative approach is based on the selection of the main molecular mechanisms underlying the early and asymptomatic HF onset that might be further prevented or antagonized through the administration of natural extracts.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107744"},"PeriodicalIF":9.1,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864637","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":"Obesity and mitochondrial uncoupling – an opportunity for the carbon monoxide-based pharmacology of metabolic diseases","authors":"Aleksandra Danielak ,&nbsp;Marcin Magierowski","doi":"10.1016/j.phrs.2025.107741","DOIUrl":"10.1016/j.phrs.2025.107741","url":null,"abstract":"<div><div>Obesity, a chronic and progressive disease with a complex etiology, remains a significant global health challenge. Despite advancements in lifestyle interventions, pharmacological therapies, and bariatric surgery, substantial barriers to effective and sustained obesity management persist. Resistance to weight loss and gradual weight regain are commonly reported, limiting the long-term success of both non-pharmacological and pharmacological strategies. A possible contributor is metabolic adaptation, a phenomenon characterized by reduced metabolic rate and energy expenditure following weight loss, which hinders therapeutic efficacy. To address these challenges, increasing attention has been directed toward strategies that counteract maladaptive mechanisms by modulating metabolic rate and enhancing energy expenditure. One promising approach involves mitochondrial uncoupling, where electron transport and oxygen consumption are disconnected from ATP synthesis, promoting energy dissipation. Preclinical studies have demonstrated the potential of various chemical compounds with uncoupling activity as anti-obesity agents. Additionally, carbon monoxide (CO) has emerged as a significant gaseous signaling molecule in human physiology, with anti-inflammatory, antioxidative, and cytoprotective properties. Advances in CO-based pharmacology have led to the development of controlled-release CO donors, enabling precise therapeutic application. Experimental studies suggest that CO modulates mitochondrial bioenergetics, induces mild mitochondrial uncoupling, and regulates mitochondrial biogenesis. By integrating these findings, this review uniquely connects scientific threads, offering a comprehensive synthesis of current knowledge while proposing innovative directions in mitochondrial, metabolic and CO-based pharmacological research. It highlights the potential of CO-based pharmacology to regulate metabolic rate, support weight loss, and address obesity-related dysfunctions, thus suggesting novel pathways for advancing obesity treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107741"},"PeriodicalIF":9.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852195","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":"Properties of FDA-approved small molecule protein kinase inhibitors: A 2025 update","authors":"Robert Roskoski Jr.","doi":"10.1016/j.phrs.2025.107723","DOIUrl":"10.1016/j.phrs.2025.107723","url":null,"abstract":"<div><div>Because of the deregulation of protein kinase action in many inflammatory diseases and cancer, the protein kinase family has become one of the most significant drug targets in the 21st century. There are 85 FDA-approved protein kinase antagonists that target about two dozen different enzymes and four of these drugs were approved in 2024 and a fifth was approved in 2025. Of these drugs, five target dual specificity protein kinases (MEK1/2), fourteen inhibit protein-serine/threonine protein kinases, twenty-one block nonreceptor protein-tyrosine kinases, and 45 target receptor protein-tyrosine kinases. The data indicate that 75 of these drugs are prescribed for the treatment of neoplasms. Seven drugs (abrocitinib, baricitinib, deucravacitinib, deuruxolitinib, ritlecitinib, tofacitinib, upadacitinib) are prescribed for the management of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 85 FDA-approved agents, about two dozen are used in the treatment of multiple diseases. The following four drugs received FDA approval in 2024 – deuruxolitinib (alopecia areata), ensartinib and lazertinib (non-small cell lung cancer), and tovorafenib (pediatric glioma) while mirdametinib was approved in 2025 for the treatment of type I neurofibromatosis (von Recklinghausen disease). Apart from netarsudil, temsirolimus, and trilaciclib, the approved protein kinase blockers are orally bioavailable. This article summarizes the physicochemical properties of all 85 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, ligand efficiency, lipophilic efficiency, polar surface area, and solubility. A total of 39 of the 85 FDA-approved drugs have a least one Lipinski rule of 5 violation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107723"},"PeriodicalIF":9.1,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855692","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":"Sirtuin3 attenuates pressure overload-induced pathological myocardial remodeling by inhibiting cardiomyocyte cuproptosis","authors":"Binghui Kong ,&nbsp;Xuehui Zheng ,&nbsp;Yang Hu ,&nbsp;Yuan Zhao ,&nbsp;Jinghan Hai ,&nbsp;Yun Ti ,&nbsp;Peili Bu","doi":"10.1016/j.phrs.2025.107739","DOIUrl":"10.1016/j.phrs.2025.107739","url":null,"abstract":"<div><div>Pathological myocardial remodelling is the initiation of pressure overload-induced heart failure, and its involvement in the associated molecular mechanisms remains to be fully elucidated. The aim of this study was to investigate whether Sirtuin3 (SIRT3) can affect pathological myocardial remodeling by regulating cellular cuproptosis and its potential mechanisms. In this study, we found that pressure overload induced pathologic myocardial remodeling in which cardiomyocytes showed a distinct cuproptosis signature accompanied by downregulation of SIRT3 expression. In vitro experiments demonstrated that copper ions reduced SIRT3 expression by 40 % (p &lt; 0.01) via lysosomal degradation. In vivo validation showed that pressure overload reduced SIRT3 expression by 35 % (p &lt; 0.01) in myocardial tissue. And SIRT3 knockdown increased pressure overload-induced pathological myocardial remodeling and cardiomyocyte cuproptosis. In contrast, cardiomyocytes-specific overexpression of SIRT3 by adeno-associated virus vectors attenuated pressure overload-induced pathologic myocardial remodeling and was unaffected by circulating levels of copper ions and hepatic and renal impairment. Mechanistically, the reduction of SIRT3 induced cardiomyocytes to become copper ion-sensitive state cells by affecting the binding of copper ion transporter proteins to microtubule-associated protein 1 light chain 3 beta(LC3B) in cardiomyocytes. Disturbance of copper ion homeostasis in cardiomyocytes leads to accumulation of copper ions in cardiomyocytes and the development of cuproptosis. These findings elucidate a novel mechanism by which SIRT3 affects cardiomyocyte death in pressure overload-induced pathologic myocardial remodeling and suggest the great potential of SIRT3-regulated cuproptosis of cardiomyocytes in the prevention or treatment of pathologic myocardial remodeling.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107739"},"PeriodicalIF":9.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859556","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":"PTPRG-AS1 regulates the KITLG/KIT pathway through the ceRNA axis to promote the malignant progression of gastric cancer and the intervention effect of Compound Kushen injection on it","authors":"Chao Wu ,&nbsp;Yifei Gao ,&nbsp;Zhengsen Jin ,&nbsp;Zhihong Huang ,&nbsp;Haojia Wang ,&nbsp;Shan Lu ,&nbsp;Siyu Guo ,&nbsp;Fanqin Zhang ,&nbsp;Jingyuan Zhang ,&nbsp;Jiaqi Huang ,&nbsp;Xiaoyu Tao ,&nbsp;Xinkui Liu ,&nbsp;Xiaomeng Zhang ,&nbsp;Leiming You ,&nbsp;Qinglin Li ,&nbsp;Jiarui Wu","doi":"10.1016/j.phrs.2025.107743","DOIUrl":"10.1016/j.phrs.2025.107743","url":null,"abstract":"<div><div>Gastric cancer (GC) is a common malignant tumor with high mortality, recurrence, and metastasis rates. Compound Kushen injection (CKI) combination chemotherapy has been clinically used for the treatment of GC in China for many years, but its underlying mechanisms of action remain unclear. Recent reports have highlighted the important role of the competing endogenous RNA (ceRNA) mechanism of noncoding RNA (ncRNA) and messenger RNA (mRNA) formation in GC and other tumors. This study aimed to investigate the effects of CKI on GC from the ceRNA perspective. We confirmed the inhibitory effect of CKI on GC in mouse models and cell lines. By examining the GC cell lines sensitive to CKI treatment, we developed the CNScore method to analyze the ceRNA network, revealing that the CKI-GC ceRNA network promotes GC proliferation and metastasis through the PTPRG-AS1/hsa-miR-421/KITLG axis. Finally, we constructed GC cell models with PTPRG-AS1 overexpression or knockdown and GC liver metastasis models and found that PTPRG-AS1 can sponge hsa-miR-421, releasing KITLG and promoting GC proliferation and metastasis through the KITLG/KIT pathway. Taken together, CKI can suppress these malignant phenotypes by regulating the PTPRG-AS1/hsa-miR-421/KITLG axis.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107743"},"PeriodicalIF":9.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844917","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":"Pleiotropic role of mGluR7/MAPK signaling in the protection of intelectin-1 against cerebral ischemia-reperfusion injury","authors":"Xiaochen Niu ,&nbsp;Bodong Wang ,&nbsp;Aizhen Zhao ,&nbsp;Wenwen Yang ,&nbsp;Ning Li ,&nbsp;Wenzhen Shi ,&nbsp;Wangrui Lei ,&nbsp;Ying Cheng ,&nbsp;Baoying Wang ,&nbsp;Yang Yang ,&nbsp;Songdi Wu ,&nbsp;Ye Tian","doi":"10.1016/j.phrs.2025.107735","DOIUrl":"10.1016/j.phrs.2025.107735","url":null,"abstract":"<div><div>Acute ischemic stroke (AIS) is a serious neurological condition with limited treatment options available. Studies have shown that levels of the protein intelectin-1 (ITLN-1) are linked to stroke severity and poor neurological outcomes. This study aimed to evaluate the role and molecular mechanisms of ITLN-1 in AIS. This study found that ITLN-1 is widely expressed in various brain regions, while ITLN-1 levels were significantly decreased in the blood and brain tissues of ischemic stroke patients. ITLN-1 overexpression reduced neuronal damage and motor deficits in transient middle cerebral artery occlusion/reperfusion (tMCAO/R) treated mice. Treatment with Rh-omentin or ITLN-1 overexpression also had a protective effect in cellular injury models. RNA-seq analysis revealed that ITLN-1 impacts specific genes and pathways, particularly those related to mGluR7. Molecular docking and CO-IP analysis confirmed that ITLN-1 directly binds to and interacts with mGluR7. The study also showed that the ITLN-1/mGluR7 axis regulates MAPK cascades (ERK and p38) to reduce cerebral oxidative stress, mitochondrial dysfunction, and cell death. Additionally, the compound AKR-501 was found to have a protective effect against cerebral ischemia by modulating the ITLN-1/mGluR7/MAPK cascades. Overall, these findings suggest that targeting ITLN-1 could be a promising therapeutic approach for managing AIS, with important clinical implications.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107735"},"PeriodicalIF":9.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859693","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}