Biochemical pharmacology最新文献

{"title":"G Protein-coupled receptors: key targets for maintaining the function of basal ganglia-thalamus-cortical circuits in Parkinson’s disease","authors":"Ji Wang ,&nbsp;Zhen Qiao ,&nbsp;Xiu Cao ,&nbsp;Huanhuan Li ,&nbsp;Yan Wang ,&nbsp;Qian Jiao ,&nbsp;Xi Chen ,&nbsp;Xixun Du","doi":"10.1016/j.bcp.2025.117303","DOIUrl":"10.1016/j.bcp.2025.117303","url":null,"abstract":"<div><div>Parkinson’s Disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, is clinically characterized by resting tremor, rigidity and postural balance disorder. Its pathological essence is the progressive degenerative death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), leading to a significant decrease in striatal dopamine (DA) levels. This results in the dysfunction of basal ganglia-thalamus-cortex (BGTC) circuit. This circuit is the core neural circuit of motor control, and its abnormality not only directly causes the motor symptoms of PD, but also participates in the cascade of disease progression through the disorder of neurotransmitter signals. At present, DA replacement therapy and DA receptors (DARs) agonists are still the main methods of clinical treatment, but single therapy cannot fully correct the imbalance of other neurotransmitter systems, which has significant limitations in long-term efficacy and symptom management. G protein-coupled receptors (GPCRs), as the largest family of membrane proteins, have become important targets for PD treatment due to their extensive participation in physiological regulatory networks and excellent drug development potential. These transmembrane signaling molecules play important roles in multiple key nodes in the pathological process of PD by precisely regulating the release of neurotransmitters, the maintenance of synaptic plasticity and the dynamic balance of neural circuits. Here, we review the transition of BGTC in the context of PD and then focus on the pathological cascade of GPCRs mediating PD in this loop. Finally, we update the clinical trials or approvals of GPCR drugs under investigation for the treatment of PD.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117303"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005872","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":"G-protein coupled receptors in neuroinflammation, neuropharmacology, and therapeutics","authors":"Aditi Singh,&nbsp;Sucharita Shadangi,&nbsp;Soumendra Rana","doi":"10.1016/j.bcp.2025.117301","DOIUrl":"10.1016/j.bcp.2025.117301","url":null,"abstract":"<div><div>The G protein-coupled receptors (GPCRs) represent one of the most pharmacologically targeted classes of seven-transmembrane (7TM) receptors, identified through whole genome sequencing of humans. GPCRs transduce extracellular stimuli and signals into intracellular responses, enabling precise cellular communication for physiology and homeostasis. Given their ability to sense a variety of ligands, GPCRs regulate a plethora of physiological functions, such as sensory perception, hormonal regulation and metabolism, growth and development, cardiovascular and reproductive regulation. GPCRs also orchestrate immune responses, triggering a balanced pro- and anti-inflammatory signaling, which is linked to the development, differentiation, and regulation of B-cells that are responsible for the secretion of infection-fighting antibodies. However, an imbalance in inflammatory signaling is also linked to disruption of B-cell differentiation, leading to autoimmune diseases due to increased levels of autoantibodies. Additionally, GPCRs modulate neurotransmission and synaptic plasticity, influencing behaviour, mood, and cognitive functions. Due to their diverse functionality, ∼40 % of FDA-approved, currently marketed drugs are reported to target different GPCRs for therapeutic benefit. A focal point of this review is GPCR-driven neuroinflammation, particularly in neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, including others. The review highlights the contribution of the pro- and anti-inflammatory GPCRs in modulating the disease pathophysiology, including the existing and emerging therapies. It also provides a future roadmap for alternative drug discovery for suppressing neuroinflammation-mediated neurodegenerative disease.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117301"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996702","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":"Design of peptide-based PAC1 antagonists combining molecular dynamics simulations and a biologically relevant cell-based assay","authors":"Wenqin Xu ,&nbsp;Abigail M. Keith ,&nbsp;Wenjuan Ye ,&nbsp;Xin Hu ,&nbsp;Noel Southall ,&nbsp;Juan J. Marugan ,&nbsp;Marc Ferrer ,&nbsp;Mark J. Henderson ,&nbsp;Patrick M. Sexton ,&nbsp;Giuseppe Deganutti ,&nbsp;Lee E. Eiden","doi":"10.1016/j.bcp.2025.117300","DOIUrl":"10.1016/j.bcp.2025.117300","url":null,"abstract":"<div><div>The PACAP receptor PAC1 is a G_s-coupled family B1 GPCR for which the highest-affinity endogenous peptide ligands are the pituitary adenylate cyclase-activating peptides PACAP38 and PACAP27, and whose most abundant endogenous ligand is PACAP38. PACAP action at PAC1 is implicated in neuropsychiatric disorders, atherosclerosis, pain chronification, and protection from neurodegeneration and ischemia. As PACAP also interacts with two related receptors, VPAC1 and VPAC2, highly selective ligands, both agonists and antagonists, for PAC1 have been sought. To date, the peptide PACAP(6–38) and polypeptide M65, which is related to maxadilan, a sandfly vasodilator peptide, have been identified as selective for PAC1. Several non-peptide small molecule compounds (SMOLs) have been reported to be specific antagonists at PAC1, albeit there is only limited literature detailing their pharmacology across different systems and within different laboratories. Here, we present a platform of cellular assays for the screening of biologically relevant antagonists at PAC1 and show that some currently proposed SMOL antagonists do not have activity in this cell reporter assay, while we confirm that PACAP(6–38) and M65 are competitive antagonists. We have used this assay system to explore other peptide antagonists at PAC1, guided by molecular dynamics analysis of the PACAP-PAC1 interaction based on cryo-EM structural models of PAC1 complexed with a number of biologically active ligands. The affinity-trap model for the PAC1-ligand interaction successfully predicts the engagement behavior of PACAP27 and PACAP38 peptide-based PAC1 inhibitors. In particular, C-terminal deletants of PACAP(6–38) that maintain equipotency to PACAP(6–38) allow the shorter sequence to function as a scaffold for further peptide-based antagonist exploration.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117300"},"PeriodicalIF":5.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145005877","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":"Alteration of alanine-327 in LXRα to LXRβ-type histidine deteriorates its subtype-selective activation by riccardin C","authors":"Norimasa Tamehiro ,&nbsp;Yukari Shigemoto-Mogami ,&nbsp;Hongyan Cui ,&nbsp;Yoshinori Asakawa ,&nbsp;Norihito Shibata ,&nbsp;Tomoko Nishimaki-Mogami","doi":"10.1016/j.bcp.2025.117304","DOIUrl":"10.1016/j.bcp.2025.117304","url":null,"abstract":"<div><div>Liver X receptors (LXRα and LXRβ) are nuclear receptors critical for lipid homeostasis and inflammation regulation, making them potential therapeutic targets for atherosclerosis and inflammatory diseases. While LXR agonists hold promise, their use is limited by adverse effects on hepatic lipogenesis. Riccardin C (RC) has shown promise as an LXRα partial agonist/ LXRβ antagonist with cell-type-selective properties. This study investigates the molecular mechanisms behind RC-induced LXRα activation. A series of LXRα/β chimera and point-mutated receptors was generated to identify the domains and residues required for RC-induced transactivation. Functional analysis revealed that mutating alanine-327 of LXRα to LXRβ-type histidine in helix 6 impaired RC-induced association with coactivator peptides, reducing transactivation. Conversely, mutating histidine-341 of LXRβ or the inactive chimera to the LXRα-type alanine partially restored the response to RC, highlighting the significance of the A327H mutation in selective LXRα activation by RC. Furthermore, in vivo experiments revealed that when administered orally to mice, RC selectively induced hepatic and intestinal <em>Abca1</em> expression without stimulating hepatic lipogenic gene expression, thereby elevating HDL levels without increasing plasma and hepatic triglycerides. These findings offer valuable insights for the development of novel therapeutic agents.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117304"},"PeriodicalIF":5.6,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999560","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":"Pharmacological characterization of ubrogepant and atogepant in cAMP assays at human, rat, and mouse calcitonin family receptors in transfected cells.","authors":"Mhairi Nimick, Tyla I Alexander, Michael L Garelja, Christopher Walker, Pradeep Banerjee, Debbie L Hay","doi":"10.1016/j.bcp.2025.117295","DOIUrl":"https://doi.org/10.1016/j.bcp.2025.117295","url":null,"abstract":"<p><p>Calcitonin gene-related peptide (CGRP) is involved in migraine pathophysiology, and can activate multiple receptors belonging to the calcitonin receptor family; this includes the CGRP receptor, adrenomedullin and amylin (AMY) receptors. Ubrogepant and atogepant, which were designed to target the CGRP receptor, are therapeutically approved for the management of migraine. However, there are limited data on their ability to antagonize members of the wider calcitonin receptor family. We therefore defined the receptor pharmacology of ubrogepant and atogepant at each of the seven calcitonin family receptors from rat, mouse and human. Cos7 cells transiently transfected with each receptor were exposed to species-matched agonists in the absence or presence of ubrogepant and atogepant. As all receptors robustly couple to the Gαs G protein, cyclic adenosine monophosphate production was measured and antagonist potency quantified. Ubrogepant and atogepant antagonized multiple rodent receptors, although the exact profile differed between compound and species. Both compounds were relatively non-selective between rat receptors, suggesting it may be difficult to interpret results in rat models. Selectivity was distinct at mouse receptors. For human receptors, both compounds were most potent at the CGRP receptor, however there was also some affinity at other receptors from this family, especially the AMY₁ receptor. Collectively, our data show that while these compounds are most potent at the CGRP receptor, they have activity at other receptors from the calcitonin receptor family, and this activity differs between species. Our data provide a framework for understanding the activity of ubrogepant and atogepant in rat, mouse and human studies.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"117295"},"PeriodicalIF":5.6,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940683","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":"Harmine suppresses pancreatic cancer through DYRK1A-mediated hyper-activated RAS/MAPK inhibition","authors":"Cen Liu ,&nbsp;Jinchai Qi ,&nbsp;Danyang Ye ,&nbsp;Shuyue Wang ,&nbsp;Jieshu Li ,&nbsp;Xiaoyu Guo ,&nbsp;Xia Li ,&nbsp;Mei Ding ,&nbsp;Yonggang Liu","doi":"10.1016/j.bcp.2025.117291","DOIUrl":"10.1016/j.bcp.2025.117291","url":null,"abstract":"<div><div>KRAS ^G12D is the most frequent RAS mutation in pancreatic cancer (PC). Recently, small molecule inhibitors like MRTX1133, which target KRAS ^G12D, have shown efficacy in inhibiting PC growth. However, the development of intrinsic and acquired resistance to these inhibitors has been observed, necessitating the identification of novel therapeutic targets. In this study, we first reported that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) could modulate the level of KRAS ^G12D-GTP depending on its phosphatase activity, and its knockdown could inhibit the hyperactivation of KRAS ^G12D. It was found that DYRK1A could be the target of harmine (HM) to regulate the activity of KRAS ^G12D/MAPK, resulting in HM inhibiting the malignant phenotypes of PC cells. To elucidate the underlying mechanism, we confirmed the interaction between DYRK1A and KRAS ^G12D using fluorescence colocalization, bimolecular fluorescence complementation (Bi-FC), and co-immunoprecipitation (Co-IP). We further established that the kinase activity was essential for DYRK1A to activate KRAS ^G12D. In addition, RNA sequencing revealed that HM induced downregulation of RAS-related pathway gene expression in PC. It was also found that HM may demonstrate anti-PC effect by inhibiting autophagy. In spite of the mechanism, we further validated the potential of DYRK1A as a therapeutic target for KRAS ^G12D-induced cancer based on <em>Caenorhabditis elegans</em> model. The loss-of-function mutation in <em>mbk-1</em> (<em>DYRK1A</em> homologous gene) could inhibit the multivulva (Muv) phenotype in nematodes with KRAS ^G12D. Collectively, our findings indicate that HM could suppress the RAS/MAPK pathway by inhibiting DYRK1A kinase activity, suggesting that DYRK1A could serve as a therapeutic target for PC treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117291"},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940770","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":"Cholesterol differentially modulates the activity of opioid and muscarinic receptors via a common binding site","authors":"Nikolai Chetverikov,&nbsp;Alena Janoušková-Randáková,&nbsp;Dominik Nelic,&nbsp;Jan Jakubík","doi":"10.1016/j.bcp.2025.117296","DOIUrl":"10.1016/j.bcp.2025.117296","url":null,"abstract":"<div><div>G protein-coupled receptors (GPCRs) are membrane proteins that represent the largest and most therapeutically targeted receptor class, accounting for 30% of currently marketed drugs. Two binding motifs for membrane cholesterol, the cholesterol recognition amino acid consensus (CRAC) domain and the cholesterol consensus motif (CCM), have been postulated. Using a simulation of the molecular dynamics of cholesterol association with the receptor, we predicted the binding of membrane cholesterol to non-canonical sites, distinct from CRAC and CCM, at muscarinic and opioid receptors. We identified a binding site common to muscarinic and opioid receptors at TM6, with arginine 6.35 as the major residue. Membrane cholesterol depletion mimics the effects of R^6.35 mutations, confirming its role in receptor modulation. Targeting cholesterol-binding sites offers novel pharmacotherapeutic strategies, including tissue-specific sterol-based modulation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117296"},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931794","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":"Piezo1 promotes colitis progression by modulating the Nrf2/NF-κB/NLRP3 signaling pathway","authors":"Pei Zhou ,&nbsp;Liwu Zeng ,&nbsp;Kai Ma ,&nbsp;Boyan Li,&nbsp;Yizhuo Zhang,&nbsp;Ziyou Zhong,&nbsp;Yaqi Wan,&nbsp;Kaixiong Tao,&nbsp;Peng Zhang","doi":"10.1016/j.bcp.2025.117293","DOIUrl":"10.1016/j.bcp.2025.117293","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is a type of chronic inflammatory disorde<strong>rs.</strong> The main pathological features of IBD include immune homeostasis disorder and intestinal epithelial barrier dysfunction, which jointly lead to the deterioration of IBD. Mechanosensation refers to the ability of an organism to sense mechanical stimuli (such as pressure, pulling and shearing forces) and make adaptive responses, which plays an important role in the peristalsis and dilation of the intestines. Piezo1 is a mechanosensitive ion channel which is highly expressed in macrophages in the lamina propria of the colon, and closely related to the development of colonic inflammatory injury. However, it remains unclear how the mechanical sensing property of Piezo1 plays a role in the occurrence and development of IBD. Therefore, we investigated the role of Piezo1 in the pathophysiology of intestinal inflammation and its effects on modulating the Nrf2/NF-κB/NLRP3 signaling pathway. Wild-type and Piezo1^fl/flLyz2^cre ulcerative colitis model was established by oral administration of 5 % dextran sulfate sodium (DSS), and the mice were monitored for changes in body weight, faeces, and other living conditions. Single-cell sequencing indicated that Piezo1 was highly expressed in macrophages from ulcerative colitis tissues. RNA sequencing showed a reduction in NFκB expression levels when Piezo1 expression was inhibited in mouse colonic lamina propria macrophages, suggesting that Piezo1 could play an important role in DSS-induced inflammatory responses in mouse colons by regulating NFκB. Piezo1 inhibitors effectively reduced pathological damage of colonic tissue, inflammatory factor release, and oxidative stress levels, such as ROS and MDA levels; aided in maintaining normal intestinal barrier function; and had significant protective effects on DSS-induced colitis in mice. This study identify the critical role of Piezo1 in colitis development in mice. Piezo1 can exacerbate inflammatory damage in colonic tissues by modulating the Nrf2/NF-κB/NLRP3 signaling pathway, thereby promoting colitis development in mice.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117293"},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931792","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":"α7nAChR activation promotes the generation of Treg cells by enhancing the dephosphorylation of Foxo1 via the IP3R/Ca2+/calcineurin pathway","authors":"Yue He ,&nbsp;Yanrong Zhu ,&nbsp;Yilei Guo ,&nbsp;Danlei Xu ,&nbsp;Jiafeng Zhang ,&nbsp;Zhifeng Wei ,&nbsp;Yufeng Xia ,&nbsp;Yue Dai","doi":"10.1016/j.bcp.2025.117290","DOIUrl":"10.1016/j.bcp.2025.117290","url":null,"abstract":"<div><div>While it is well documented that acetylcholine released through vagus nerve stimulation can enhance the differentiation of regulatory T cells (Treg cells) and alleviate symptoms of multiple autoimmune diseases by targeting the α7 nicotinic acetylcholine receptor (α7nAChR), the underlying mechanisms remain elusive. Here, we show that α7nAChR activation by agonists promoted Treg cell differentiation <em>in vitro</em>. Mechanistically, α7nAChR facilitates the recruitment of forkhead box O1 (Foxo1) to the forkhead box P3 (Foxp3) promoter by enhancing calcineurin activity, which increases the dephosphorylation of Foxo1 at Ser319. Moreover, α7nAChR activation augments calcineurin activity through the activation of the inositol 1,4,5-trisphosphate receptor (IP3R), which in turn facilitates calcium ion release from the endoplasmic reticulum. The promotion of α7nAChR on the generation of Treg cells in the spleens, mesenteric lymph nodes and lamina propria of colon mucosa in colitis mice is nearly completely reversed by pretreatment of either AAV-shα7nAChR or AAV-shIP3R. In summary, α7nAChR promotes the generation of Treg cells by recruiting <em>Foxo1</em> to the <em>Foxp3</em> promoter <em>via</em> the IP3R/Ca2+/calcineurin pathway, and α7nAChR and IP3R may serve as promising therapeutic targets for Treg cell deficiency-related diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117290"},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940730","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":"Next-generation nanoparticles for cancer and autoimmune therapy","authors":"Alshayma N. Al-Thani ,&nbsp;Asma Ghafoor Jan ,&nbsp;Zainab Hajialthakar ,&nbsp;Ahmed Awad ,&nbsp;Mohamed Abbas","doi":"10.1016/j.bcp.2025.117298","DOIUrl":"10.1016/j.bcp.2025.117298","url":null,"abstract":"<div><div>Immune modulation is a critical therapeutic approach for cancer and autoimmune diseases, aiming to balance immune activation and suppression within specific disease environments. Next-generation nanoparticles (NPs) offer a promising method for precisely delivering cytokines and other immune modulators, addressing challenges such as systemic toxicity and limited specificity. This review explores the dual function of NPs in modulating pro- and anti-inflammatory responses, enhancing immune detection and tumor elimination in cancer, while promoting immune tolerance in autoimmune diseases. Advanced NP design strategies are highlighted, including stimuli-responsive systems tailored for the tumor microenvironment (TME) and inflamed tissues, as well as co-delivery platforms that combine cytokines with immune checkpoint inhibitors (ICIs). Additionally, dual-function NPs designed to target multiple immune pathways simultaneously are examined, offering innovative solutions for complex diseases. Despite ongoing challenges related to compatibility, safety, and scalability, the integration of nanotechnology with immune modulation presents significant potential to transform therapeutic outcomes. Future research should focus on overcoming these limitations to enhance clinical applications. By leveraging the precision and adaptability of next-generation NPs, a new frontier in immune therapy is emerging, offering more effective and targeted treatments for cancer and autoimmune diseases.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117298"},"PeriodicalIF":5.6,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144922975","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}