British Journal of Pharmacology最新文献

{"title":"Inhibition of the NR4A1-mediated cell cycle checkpoint enhances hyperplastic adipogenesis and glucose homeostasis in obesity.","authors":"Wanning Qiao, Cun Ku, G V Naveen Kumar, Jonathan D Brown, Manni Wu, Chenhang Li, Jiyu Xie, Huicui Meng, Litao Sun, Tao Zhou, Dong Liang, Yiwei Li, Matthew L Steinhauser, Yang Zhang","doi":"10.1111/bph.70655","DOIUrl":"https://doi.org/10.1111/bph.70655","url":null,"abstract":"<p><strong>Background and purpose: </strong>The nuclear receptor NR4A1 is a critical node in transcriptional circuits for metabolic adaptation, yet its role in adipocyte progenitor (AP) fate and proliferation is unclear. We sought to define how NR4A1 governs early adipogenesis and adipose tissue plasticity.</p><p><strong>Experimental approach: </strong>Doxycycline-inducible NR4A1-overexpressing and NR4A1-deficient 3T3-L1 models were used to assess lipid accumulation, mitotic clonal expansion (MCE), and cell-cycle dynamics. Multiomics integration (RNA-seq and chromatin assays) identified NR4A1 targets. The functionality of two lead candidates, ANLN and CDC20, was tested by genetic knockdown and pharmacological inhibition. Diet-induced obese mice received the NR4A1 antagonist C-DIM8 alone or combined with the PPARγ agonist rosiglitazone to evaluate adipose expansion and metabolic outcomes.</p><p><strong>Key results: </strong>NR4A1 exerted a stage-specific inhibitory effect during early differentiation, reducing expression of canonical adipogenic markers and lipid accumulation. Integrative transcriptomic and chromatin analyses identified Anln and Cdc20 as direct NR4A1 targets essential for MCE. Depletion of either gene phenocopied NR4A1 overexpression, inducing G2/M arrest and blunting of adipogenesis. Pharmacological CDC20 inhibition with Apcin suppressed preadipocyte proliferation and differentiation in a dose-dependent manner. Importantly, in a diet-induced obese mouse model, combined treatment with the NR4A1 antagonist C-DIM8 and the PPARγ agonist rosiglitazone promoted AP proliferation, hyperplastic adipose tissue expansion, and improved glucose tolerance.</p><p><strong>Conclusions and implications: </strong>NR4A1 functions as a transcriptional gatekeeper of adipogenic initiation by restraining the Anln/Cdc20 cell-cycle program. Pharmacological modulation of the NR4A1-cell-cycle axis, particularly alongside PPARγ activation, may offer a strategy to augment adipose tissue plasticity and metabolic resilience in obesity.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104469","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 medial prefrontal cortex-ventral tegmental area dopaminergic circuit regulates the pleasure of tactile contact by releasing dopamine in the nucleus accumbens.","authors":"Jinhe Zhai, Zihan Xu, Xinran Yu, Keqing Shi, Xiaoyan Zhang, Hiroshi Kuniishi, Min Jue Xie, Yuying Zhang, Xueke Yao, Xinxin Wang, Xuan Cao, Xinyi Zhang, Dongxin Li, Jie Zhang, Yi Xu, Lili Fan, Lijie Wu, Jia Wang","doi":"10.1111/bph.70690","DOIUrl":"https://doi.org/10.1111/bph.70690","url":null,"abstract":"<p><strong>Background and purpose: </strong>Tactile contact during social interactions is believed to enhance the experience of pleasure. Dopaminergic neurons in the ventral tegmental area (VTA) are crucial for the regulation of pleasurable emotions. We aim to reveal the specific circuit mechanisms by which the VTA contributes to pleasure derived from tactile contact.</p><p><strong>Experimental approach: </strong>Paradigms of social interaction in the presence of physical contact (SIPPC) and social interaction in the absence of physical contact (SIAPC) were established. The expression of c-fos in different brain regions was detected by immunofluorescence. A combination of behavioural tests, fibre-optic calcium imaging, chemogenetics, patch-clamp techniques and molecular biological methods were used to investigate the circuit mechanism mediating pleasure of tactile contact.</p><p><strong>Key results: </strong>Dopaminergic neurons in the VTA were implicated in triggering pleasurable emotions associated with SIPPC. Mechanistically, SIPPC promoted the disinhibition of presynaptic neurons and enhanced excitatory synaptic transmission. Furthermore, projections from the mPFC to VTA dopaminergic neurons were activated during SIPPC. Chemogenetic activation of the mPFC-VTA^DA circuit increased SIPPC-induced pleasure, whereas its inhibition decreased it. SIPPC triggered dopamine release in the nucleus accumbens (NAc), where the inhibition of dopamine receptors (D₁R) can reverse the pleasure-promoting effect of mPFC-VTA^DA circuit activation during SIPPC.</p><p><strong>Conclusions and implications: </strong>Collectively, these findings elucidate the key roles and mechanisms by which VTA^DA neurons receive projections from the mPFC and subsequently release dopamine in the NAc to regulate the pleasure induced by tactile contact, which provide new insights into the mechanisms underlying the association between tactile and social interaction.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104503","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":"Direct targeting of LYN kinase by fluphenazine triggers ferroptosis to suppress lung adenocarcinoma.","authors":"Yuna Shao, Huiling Zhang, Chenying Shu, Yihua Zhang, Di Lu, Ying Wang, Liying Zhang, Yang Yang, Lei Gu, Jianjun Li, Jianjie Zhu, Yuanyuan Zeng, Zhaowei Yan, Zeyi Liu","doi":"10.1111/bph.70686","DOIUrl":"https://doi.org/10.1111/bph.70686","url":null,"abstract":"<p><strong>Background and purpose: </strong>Lung adenocarcinoma (LUAD) is an aggressive malignancy with a poor prognosis. Current therapies often cause significant side effects and result in poor patient tolerance, underscoring the need for safer and more efficient treatment strategies. Repurposing central nervous system (CNS) drugs-known for their established safety and blood-brain barrier (BBB) permeability-offers a promising alternative.</p><p><strong>Experimental approach: </strong>Using Connectivity Map analysis, we identified the antipsychotic agent fluphenazine (Flu) as a potential anti-LUAD candidate. We then investigated the mechanism of action of Flu in LUAD, including its target protein, binding site and downstream signalling pathways, as well as its induction effect on ferroptosis in LUAD cells.</p><p><strong>Key results: </strong>Flu acts as a lck/yes-related protein tyrosine kinase (LYN) kinase inhibitor, exerting both anti-proliferative and anti-metastatic effects in LUAD. Leu253 of LYN was identified as a critical binding site for Flu. Notably, LYN is highly expressed in lung cancer. Further investigation revealed that Flu induces ferroptosis in LUAD cells; mechanistically, Flu directly inhibits LYN, attenuates downstream focal adhesion kinase (FAK) signalling and significantly down-regulates glutathione peroxidase 4 (GPX4).</p><p><strong>Conclusion and implications: </strong>This study unveils a novel mechanism by which Flu suppresses LUAD through the LYN-FAK-GPX4 axis, supporting CNS drug repurposing and highlighting the value of BBB-penetrant drugs for LUAD treatment. Our findings identify LYN as a new therapeutic target and Flu as a candidate drug for targeted ferroptosis induction in LUAD.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104317","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":"Sinapine thiocyanate (ST) ameliorates endothelial cell dysfunction by targeting chloride intracellular channel 4 (CLIC4) to treat hypoxia-induced pulmonary hypertension.","authors":"Xiaowei Gong, Yuming Wang, Shiwei Kang, Ziping Zhang, Xin Liu, Weibo Wen, Yanling Sheng, Yadong Yuan, Huantian Cui, Feitian Min","doi":"10.1111/bph.70676","DOIUrl":"https://doi.org/10.1111/bph.70676","url":null,"abstract":"<p><strong>Background and purpose: </strong>Sinapine thiocyanate (ST) has effects in treating respiratory diseases. Its action in hypoxic pulmonary hypertension (HPH) remains poorly understood. We evaluated the potential of ST on HPH and its molecular mechanism.</p><p><strong>Experimental approach: </strong>ST was evaluated on a rat model HPH. Single-cell RNA sequencing (scRNA-seq) identified ST-modulated cell clusters. ST regulation on endothelial dysfunction-induced neutrophil migration in vivo and in vitro was studied. Molecular docking, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) analysis were used to identify targets of ST. The molecular mechanism by which ST modulates endothelial cell dysfunction through gene silencing experiments was also investigated.</p><p><strong>Key results: </strong>ST significantly reduced pulmonary arterial pressure in HPH rats and alleviated pathological changes in lung tissue. scRNA-seq showed that ST markedly decreased the proportion of neutrophils, down-regulated the expression of their cell migration-related genes and the gene expression of chemokines in endothelial cells. In vivo experimental indicated that ST reduced neutrophil infiltration in lung tissue and lowered inflammatory cytokine levels in bronchoalveolar lavage fluid. Further in vitro studies indicated that ST reduced neutrophil migration by inhibiting hypoxia-induced endothelial dysfunction. ST inhibited P65 phosphorylation-mediated endothelial dysfunction by targeting chloride intracellular channel 4 (CLIC4). Inhibiting CLIC4 activation through blocking the cascade reaction of CLIC4 up-regulation and activation induced by pro-inflammatory cytokines. Silencing endothelial cell CLIC4 abolishes ST inhibitory effects on inflammatory cytokine expression and regulatory impact on P65 activation.</p><p><strong>Conclusions and implications: </strong>ST targeted CLIC4 inhibits NF-κB p65 activation would have therapeutic effects against HPH.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104494","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":"Positive modulation of glucagon-like peptide 1 (GLP-1) receptor by endogenous haemorphins with implications in glucose metabolism and diabetes.","authors":"Farheen Badrealam Khan, Rwdah Mohamed Alameri, Yasir S Raouf, Damien Maurel, Naiem Ahmad Wani, Anatoliy Shmygol, Irfa Anwar, Heng B See, Elizabeth K M Johnstone, Elodie Dupuis, Eric Trinquet, Kevin D G Pfleger, Emilia Oueis, Mohammed Akli Ayoub","doi":"10.1111/bph.70677","DOIUrl":"https://doi.org/10.1111/bph.70677","url":null,"abstract":"<p><strong>Background and purpose: </strong>Haemorphins are known to target G protein-coupled receptors and their reduced serum levels were associated with diabetes and obesity. This is consistent with inhibitory action on dipeptidyl peptidase IV, controlling GLP-1 levels. The modulation of the GLP-1 receptor by haemorphins as a mechanism for regulating glucose homeostasis was investigated.</p><p><strong>Experimental approach: </strong>The effect of LVV-haemorphin 7 (LVV-H7) on GLP-1 receptor was assessed in human embryonic kidney (HEK293) and rat insulinoma (INS-1 832/3) cells using bioluminescence resonance energy transfer, downstream signalling, cell viability, insulin synthesis experimental and computational ligand binding analysis.</p><p><strong>Key results: </strong>LVV-H7 has positive action on GLP-1 receptor occurring with GLP-1 but not orforglipron (LY3502970), indicating a peptide-peptide interaction, causing a left shift in GLP-1's dose responses. LVV-H7 also potentiated GLP-1-induced insulin expression and its protective effect against glucose-induced cytotoxicity. Moreover, LVV-H7 slightly reduced the GLP-1's association kinetics with no impact on its binding properties. Molecular docking supported by functional analysis showed the existence of a putative 'allosteric' binding site at the junction between the helical and the extracellular domains (ECDs) and highlighted the critical role of Trp6 of LVV-H7 and Ser31^ECD/Glu34^ECD/Arg299^ECL2/Asp372^ECL3/Arg380^ECL3/™⁷of GLP-1 receptor. This also demonstrated that active GLP-1/GLP-1 receptor complex is required for the positive action of LVV-H7.</p><p><strong>Conclusions and implications: </strong>LVV-H7 is active on the GLP-1 receptor-mediated metabolic pathways in pancreatic β-cells. This is consistent with reduced serum haemorphin levels in diabetes/obesity, suggesting implications in glucose homeostasis. This constitutes the first Class B GPCR modulated by haemorphins, illustrating the role of haemorphin-GPCR axis in physiology/pathophysiology.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079883","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":"Structural and biochemical basis for retinol-binding protein 4 antagonism by tinlarebant.","authors":"Marco Bassetto, Philip D Kiser","doi":"10.1111/bph.70687","DOIUrl":"10.1111/bph.70687","url":null,"abstract":"<p><strong>Background and purpose: </strong>Retinol-binding protein 4 (RBP4) is a member of the lipocalin superfamily that is connected to disease states such as insulin resistance, fatty liver disease and ocular disorders including Stargardt disease. Several retinoid and non-retinoid antagonists of this protein have been developed for potential clinical use, but none have yet received FDA approval. Tinlarebant, a derivative of the early lead RBP4 antagonist, A1120, was reported to slow macular lesion growth in Stargardt disease patients. However, its precise mechanism of RBP4 antagonism remains undisclosed.</p><p><strong>Experimental approach: </strong>The binding of tinlarebant to RBP4 was studied with fluorescence spectroscopy and crystallography. The impact of tinlarebant occupancy in the RBP4 retinol-binding pocket on RBP4 complexation with transthyretin (TTR) was studied by size-exclusion chromatography. The impact of tinlarebant on plasma RBP4 levels was studied in mice.</p><p><strong>Key results: </strong>Fluorescence quenching assays demonstrate that tinlarebant competitively displaces retinol from holo-RBP4 with an IC₅₀ of 8.75 ± 0.38 nM. The RBP4-tinlarebant complex fails to associate with transthyretin in vitro. Administration of single doses of tinlarebant to mice reduced plasma RBP4 levels by up to 93%. The crystal structure shows that tinlarebant impedes RBP4 association with transthyretin through both conformational and steric effects.</p><p><strong>Conclusion and implications: </strong>Tinlarebant is a tight-binding RBP4 antagonist that lowers RBP4 plasma levels due to disruption of the RBP4- transthyretin interaction. The crystal structure shows that tinlarebant integrates multiple aspects of RBP4 interaction and antagonism found in its predecessors. Together, these data illuminate the pharmacology of a clinical inhibitor of the RBP4-retinol transport system.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079865","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":"Tracking and understanding intra- and intercellular second messengers signalling in pharmacology.","authors":"Robert Lukowski, Helmut Bischof, Miriam M Cortese-Krott","doi":"10.1111/bph.70674","DOIUrl":"https://doi.org/10.1111/bph.70674","url":null,"abstract":"","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079880","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 dual incretin agonist tirzepatide blunts nicotine-induced behaviours and neurochemistry in male mice.","authors":"Christian E Edvardsson, Thaynnam A Emous, Sarah Witley, Mia Ericson, Louise Adermark, Elisabet Jerlhag","doi":"10.1111/bph.70678","DOIUrl":"https://doi.org/10.1111/bph.70678","url":null,"abstract":"<p><strong>Background and purpose: </strong>Nicotine dependence remains one of the leading causes of morbidity and mortality worldwide, with high relapse rates and post-cessation weight gain representing persistent barriers to sustained abstinence. The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have emerged as novel treatment targets, as they appear to influence both reward-related behaviours associated with addictive substances and body weight regulation. Whether recently developed multi-receptor incretin agonists such as tirzepatide, a long-acting dual GIP/GLP-1 receptor agonist, affect nicotine-induced behaviours remains unstudied.</p><p><strong>Experimental approach: </strong>We investigated whether tirzepatide affects nicotine-induced behaviours (locomotor stimulation and expression of locomotor sensitisation, expression and reinstatement of conditioned place preference) and related neurochemistry (in vivo microdialysis and ex vivo tissue neurochemical analysis) in male mice.</p><p><strong>Key results: </strong>Tirzepatide attenuated nicotine-induced locomotor stimulation in a dose-related manner, and reduced nicotine-induced place preference, and in vivo accumbal dopamine release. Furthermore, tirzepatide suppressed reinstatement of nicotine place preference and prevented the expression of locomotor sensitisation, indicating effects beyond acute reward processing. Ex vivo neurochemical analysis of addiction-related brain regions in nicotine-sensitised mice revealed that tirzepatide blocked nicotine-induced dopamine elevations in the nucleus accumbens, ventral tegmental area and lateral septum. Furthermore, tirzepatide restored levels of multiple neurotransmitter systems, such as GABA, in a brain region-specific manner, suggesting possible effects beyond dopaminergic signalling alone.</p><p><strong>Conclusions and implications: </strong>Collectively, these findings indicate that tirzepatide attenuates nicotine-induced locomotor stimulation and dopamine release, as well as the expression and reinstatement of place preference, and the expression of locomotor sensitisation, in mice.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073612","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":"Phloroglucinol inhibits human ureteral contractions via activation of cAMP-PKA pathway.","authors":"Hanwen Liu, Ruize Xu, Zihan Guan, Lei Liu, Guangda Lv, Weibo Chen, Jiliang Wen, Jianing Liu, Jieke Yan, Fangxin Gong, Pan Xiao, Xiulin Zhang, Lei Zhang","doi":"10.1111/bph.70672","DOIUrl":"https://doi.org/10.1111/bph.70672","url":null,"abstract":"<p><strong>Background and purpose: </strong>Phloroglucinol is used to treat renal colic, especially when non-steroidal anti-inflammatory drugs are contraindicated. This study aimed to clarify its mechanism by examining effects on human ureteral contractility and underlying signalling pathways.</p><p><strong>Experimental approach: </strong>Urinary levels of neurokinin A (NKA), substance P (SP), 5-hydroxytryptamine (5-HT) and PGE₂ were measured in patients after acute renal colic. Human ureteral tissues from organ donors were studied in organ baths and myosin light chain (MLC) phosphorylation in human ureteral smooth muscle cells (hUSMCs) was assessed as a marker of contractile activity.</p><p><strong>Key results: </strong>Urinary NKA, SP and 5-HT but not PGE₂ were significantly increased in patients with colic. Phloroglucinol concentration-dependently inhibited rises in the basal tone during spasmic contractions evoked by high concentrations of KCl, NKA and 5-HT. Phloroglucinol also attenuated the frequency of spontaneous or low concentrations of NKA-evoked (30-100 nM) and 5-HT-evoked (3-10 μM) phasic contractions. The above inhibitory effects of phloroglucinol were significantly attenuated in the presence of SQ22536 (adenylate cyclase inhibitor) or H89 (PKA inhibitor). Although phloroglucinol attenuated EFS-evoked (neurogenic) contractions, this effect was markedly weaker than that observed for myogenic contractions. Phloroglucinol increased intracellular levels of cAMP and PKA in hUSMCs, and reduced the enhanced MLC phosphorylation evoked by NKA (10 μM) and 5-HT (100 μM).</p><p><strong>Conclusions and implications: </strong>These findings support the clinical use of phloroglucinol in treating renal colic, inhibiting ureteral spasm contractions via the activation of cAMP-PKA signalling and provides a rationale for its potential utility in facilitating stone expulsion.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073569","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":"Low-dose antiangiogenic multikinase inhibitor AL3810 synergizes with PD-1 blockade by reducing CSF1-driven MHC-II^int tumour-associated macrophages to optimize TIM-3⁺ CD8⁺ T-cell effector function.","authors":"Kun Fang, Wen-Xin Zhang, Zi-Han Li, Rong Wang, Yi-Ming Sun, Yi Su, Ying-Lei Gao, Min Yao, Jian Ding, Yi Chen, Yan-Fen Fang","doi":"10.1111/bph.70664","DOIUrl":"https://doi.org/10.1111/bph.70664","url":null,"abstract":"<p><strong>Background and purpose: </strong>Antiangiogenic multikinase inhibitors (AAMKIs) with PD-1/PD-L1 blockade have been approved to treat certain solid tumours. Their synergy mechanisms remain largely unknown. AL3810 (lucitanib), a AAMKI in Phase II trials, has demonstrated clinical activity. We aim to elucidate the immune modulatory effects of AL3810 and provide a rationale for its combination with immunotherapy.</p><p><strong>Experimental approach: </strong>Murine colorectal cancer models (CT26/MC38) were used. Immunofluorescence/histochemistry, flow cytometry and mass cytometry were used to explore the modulation of AL3810 alone or combined with anti-PD-1 on the tumour microenvironment (TME). Myeloid antigen-presenting cells (APCs) were sorted and co-cultured with pre-activated OT-1 CD8⁺ T-cells to evaluate their effect on CD8⁺ T-cell differentiation.</p><p><strong>Key results: </strong>Low-dose AL3810 pruned aberrant vessels and increased pericyte coverage, whereas high-dose caused severe hypoxia and reduced CD8⁺ T-cell infiltration. Through CSF1R inhibition, low-dose AL3810 reduced MHC-II^int tumour-associated macrophages, which impaired the function and survival of TCF-1^-TIM-3⁺ CD8⁺ T-cells. Meanwhile it preserved MHC-II^high TAMs and conventional dendritic cells, which triggered TCF-1⁺TIM-3^- CD8⁺ T-cells differentiated into functionally stronger and more viable TCF-1^-TIM-3⁺ CD8⁺ T-cells. Consistently, the increased expansion and enhanced cytotoxic potential of TCF-1^-TIM-3⁺ CD8⁺ T-cells underpinned the synergistic antitumour efficacy of low-dose AL3810 combined with αPD-1. Additionally, low-dose AL3810 upregulated co-stimulatory receptors on tumour-infiltrating CD8⁺ T-cells, providing potential targets to further optimize the regimen.</p><p><strong>Conclusions and implications: </strong>These findings indicate a novel immunomodulatory mechanism of low-dose AL3810, indicating ability to reprogram APC-CD8⁺ T-cell interactions, a critical axis of immune regulation, supporting its rational combination with PD-1 blockade in CRC treatment.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073599","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}