Acta Pharmacologica Sinica最新文献

{"title":"Development of XYD113 as a potent and highly selective GSPT1 degrader for cancer therapy.","authors":"Hui Shen, Xiao-Yu Luo, Xin-Yi Jing, Wei-Qin Jin, Hong-Rui Xu, Jian-Kang Hu, Zhi-Xin Zhong, Jian Zhang, Hao-Zhao Liang, Xiao-Xi Zhuang, Hong-Hua Ge, Jeff B Smaill, Jin-Xin Xu, Yan Zhang, Adam V Patterson, Jin-Ming Ma, Yong Xu","doi":"10.1038/s41401-026-01856-z","DOIUrl":"10.1038/s41401-026-01856-z","url":null,"abstract":"<p><p>G₁ to S phase transition 1 (GSPT1) represents a promising yet historically challenging therapeutic target for MYC-driven malignancies. Herein, we identified XYD113, a potent and highly selective GSPT1-targeting molecular glue degrader. XYD113 exhibits significant antiproliferative activity (IC₅₀ < 100 nM) against multiple MYC-overexpressing cancer cell lines (22Rv1, MV4-11, MOLM-16, Calu-1, HS-SY-II), and induces GSPT1 degradation in a dose- and time-dependent manner, with potency comparable to that of the clinical candidate MRT-2359. It also exhibits excellent selectivity without degrading common glutarimide analog substrates (such as SALL4, IKZF1/2/3, or CK1α). Mechanistically, XYD113 acts as a molecular glue to facilitate CRBN-GSPT1 ternary complex formation, mediating GSPT1 degradation via the UPS in a CRBN-dependent manner. Additionally, XYD113 demonstrates favorable stability in liver microsomes. Notably, XYD113 effectively downregulates the expression of genes critical for the initiation and progression of prostate cancer. In vivo, oral administration of XYD113 (5 mg/kg, daily for 21 days) significantly inhibited 22Rv1 xenograft growth (TGI = 46%) and showed a favorable safety profile in BALB/c-nude mice. Together, these findings highlight XYD113 as a promising therapeutic degrader worthy of further development for the treatment of MYC-driven cancers.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"3059-3068"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF3/SOX11-regulated FST activates IGF1R-ERK/AKT-Sp1 signaling to sustain trigeminal neuropathic pain.","authors":"Yue-Juan Ling, Bing Zhu, Zuo-Hao Yao, Ling-Jie Ma, Lin-Peng Zhu, Jing Zhang, Fei-Fei Xu, Hao Wu, Lu-Lu Ji, Yong-Jing Gao","doi":"10.1038/s41401-026-01879-6","DOIUrl":"10.1038/s41401-026-01879-6","url":null,"abstract":"<p><p>Trigeminal neuropathic pain (TNP) is a severe facial pain disorder whose pathogenesis is incompletely understood. We previously identified follistatin (FST) as a contributor to peripheral nerve injury-induced neuropathic pain through direct binding to the insulin-like growth factor-1 receptor (IGF1R) in the dorsal root ganglia. However, the regulatory mechanisms governing FST expression and its specific role in TNP remain unclear. Here, we report that FST is upregulated in trigeminal ganglion (TG) neurons following partial infraorbital nerve transection (pIONT), and that this process is regulated by the transcription factors ATF3 and SOX11. Genetic deletion or knockdown of Fst attenuated pIONT-induced TNP and reduced TG neuronal hyperexcitability. Intra-TG injection of FST promoted pain-like behaviors and activated ERK and AKT signaling in an IGF1R-dependent manner. In addition, FST decreased voltage-gated potassium (K_v) channel currents and enhanced neuronal excitability via IGF1R-ERK/AKT signaling. Notably, FST upregulated a cohort of genes, including Fst itself, Cyp26a1, and Ccl2, through the transcription factor Specificity Protein 1 (Sp1). Consistently, pIONT increased Sp1 phosphorylation, and pharmacological inhibition or knockdown of Sp1 alleviated mechanical allodynia, reduced the expression of Fst, Cyp26a1, and Ccl2, and decreased the excitability of TG neurons. Collectively, these results reveal a previously unknown mechanism by which FST activates IGF1R-ERK/AKT signaling to decrease K_v channel currents and promote Sp1-regulated gene expression, contributing to peripheral sensitization and TNP pathogenesis. Our data indicate that targeting the FST-IGF1R-ERK/AKT-Sp1 axis may represent a promising therapeutic strategy for TNP.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2908-2923"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KCNE2 upregulation improves cardiac function by inhibiting Smurf1-mediated SERCA2a degradation in diabetic cardiomyopathy in mice.","authors":"Ming Song, Kai-Ping Gao, Jie Yang, Yu-Qi Tu, Yi-Xin Zhu-Ge, Wan-Wen Cheng, Gang Wang, Ying Li, Wen-Juan Liu, Jie Liu","doi":"10.1038/s41401-026-01888-5","DOIUrl":"10.1038/s41401-026-01888-5","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM) is associated with impaired calcium handling and downregulation of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a), though the underlying regulatory mechanisms remain poorly understood. Here, we identify KCNE2, an auxiliary β-regulatory subunit of multiple ion channels, as a key regulator of SERCA2a protein stability in the diabetic heart. KCNE2 expression was significantly reduced in high fat diet/streptozotocin-induced diabetic mice and palmitic acid-treated cardiomyocytes. Using LC-MS/MS and co-immunoprecipitation, SERCA2a was identified as a direct binding partner of KCNE2. Knockdown of KCNE2 decreased SERCA2a protein levels without affecting its transcription. Cardiac-specific overexpression of KCNE2 via adenovirus-associated virus 9 delivery restored SERCA2a expression, improved sarcoplasmic reticulum Ca²⁺ cycling, and ameliorated systolic and diastolic dysfunction in diabetic mice. Mechanistically, KCNE2 competitively inhibited the interaction between SERCA2a and the E3 ubiquitin ligase Smurf1, thereby suppressing Smurf1-mediated polyubiquitination and proteasomal degradation of SERCA2a. These results reveal a novel protective role of KCNE2 in diabetic hearts and propose KCNE2 upregulation as a potential therapeutic strategy for DCM. Upregulation of KCNE2 ameliorates cardiac dysfunction by reducing Smurf1-mediated SERCA2a polyubiquitination and degradation, and re-establishes SR Ca²⁺ homeostasis in DCM.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2955-2968"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMAL1 silencing as a promising chemosensitizing strategy for triple-negative breast cancer.","authors":"Lu-Yi Wang, Xue-Han Xu, Wen-Jing Xuan, Xin-Yue Bi, Qin Zhou","doi":"10.1038/s41401-026-01788-8","DOIUrl":"10.1038/s41401-026-01788-8","url":null,"abstract":"<p><p>Circadian genes are closely associated with tumor development and its sensitivity to chemotherapeutic agents. In triple-negative breast cancer (TNBC), the core circadian gene BMAL1 exhibits an aberrant expression pattern, but its mechanism of influencing TNBC chemosensitivity remains unknown. In this study, we demonstrate that BMAL1 acts as an oncogene in TNBC. Using BMAL1 siRNA-loaded lipid nanoparticles (LNPs), we effectively silenced BMAL1 expression both in vitro and in vivo, resulting in enhanced apoptosis and reduced proliferation of TNBC cells. Notably, BMAL1 suppression following chemotherapy-induced DNA damage impairs the RPA-ATR-CHK1 DNA repair axis, leading to S-phase arrest and accumulation of unrepaired DNA damage. This synergistically increases the sensitivity of TNBC cells to etoposide. Our findings reveal BMAL1 as a promising therapeutic target and support the potential of silencing BMAL1 with siRNA as a neoadjuvant strategy in combination with chemotherapeutic agents for the treatment of TNBC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2996-3008"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Penfluridol directly targets PDPK1 to suppress AKT1 phosphorylation and stabilize CTR1, inducing cuproptosis in colorectal cancer.","authors":"Ke-Min Ni, Hua-Qing Wang, Xiao-Fei Shi, Qing Yu, Xin-Tong Dai, Ji-Yan Wang, Ming-Ming Sun, Qi Yan, Xin-Ru Zhai, Yan-Fei Liu, Kai-Long Zhao, Wan-Ting Wang, Meng-Wei Fu, Xiao-Tong Wang, Shi-Yu Fang, Jie Zhang, Hua-Miao Wang, Chang-Liang Shan, Shuai Zhang, Chun-Ze Zhang","doi":"10.1038/s41401-026-01806-9","DOIUrl":"10.1038/s41401-026-01806-9","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a major cause of cancer mortality worldwide. Here, we identified the antipsychotic drug penfluridol as a potent anticancer agent that induces cuproptosis in CRC through a newly defined signaling mechanism. Using real-world clinical datasets, we demonstrated that PDPK1 is significantly upregulated in CRC and further increases in its expression level are correlated with a worse outcome, whereas CTR1 is downregulated in CRC and further decreases in its expression level are correlated with favourable outcomes, directly establishing the clinical relevance of these two proteins to CRC. Mechanistically, drug affinity responsive target stability assays revealed PDPK1 as a direct binding target of penfluridol. Penfluridol inhibited PDPK1 kinase activity and reduced AKT1 phosphorylation, which in turn decreased CTR1 ubiquitination and stabilized CTR1 on the plasma membrane. Enhanced CTR1 expression promoted intracellular copper influx, leading to copper overload and cuproptosis. Functionally, penfluridol suppressed CRC growth in cell lines, patient-derived organoids, and PDX models and was well-tolerated with limited systemic toxicity. Genetic and pharmacologic modulation confirmed that the PDPK1-p-AKT1-CTR1 axis governs copper homeostasis and mediates penfluridol-induced cell death. Collectively, our findings revealed a previously unrecognized link between oncogenic kinase signaling and copper metabolism, established PDPK1 and CTR1 as clinically relevant biomarkers, and provided a strong rationale for repurposing penfluridol as a dual-function therapeutic that induces cuproptosis and enhances chemosensitivity in colorectal cancer.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"3009-3023"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148012989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sweetening the bonds: how O-GlcNAcylation modulates cell adhesion.","authors":"Wen-Hui Lou, Guo-Hong Qiao, Zi-Jun Wei, Yu-Qin Hu, Yang Li, Qi-Jie Zhao, Shi-Sheng Zhou, Yue Wang, Bei Chen, Zhi-Wei Xu, Xiang Chen","doi":"10.1038/s41401-026-01844-3","DOIUrl":"10.1038/s41401-026-01844-3","url":null,"abstract":"<p><p>O-GlcNAcylation is a dynamic, reversible post-translational modification that attaches N-acetylglucosamine (GlcNAc) to the serine or threonine residues of intracellular proteins. Catalysed by O-GlcNAc transferase and removed by O-GlcNAcase, this modification acts as a key nutrient and stress sensor. Although cell adhesion is fundamental to tissue architecture and mechanotransduction, emerging evidence has shown that O-GlcNAcylation profoundly orchestrates these processes. By modulating the composition and signalling of adhesion complexes, O-GlcNAcylation regulates both cell-cell and cell-matrix interactions. Through crosstalk with phosphorylation, this modification drives cellular adhesion plasticity, with broad implications for development, immunity, and diseases, such as cancer and neurodegeneration. Recent advances revealed that O-GlcNAcylation fine-tunes key regulators, including Focal Adhesion Kinase (FAK), Zyxin, and integrins, to control focal adhesion turnover. These mechanistic insights pave the way for novel therapeutic strategies targeting glycosylation-dependent adhesion signalling.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2709-2721"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dual-antigen mRNA-lipid polyplex vaccine elicits durable multistage immunity and sterile protection against malaria in mice.","authors":"Xiaoxing Wang, Aiai Wang, Wenqi Huang, Penghai Tian, Long Cao, Bo Xiao, Jipin Han, Zhenghui Huang, Lubin Jiang","doi":"10.1038/s41401-026-01850-5","DOIUrl":"10.1038/s41401-026-01850-5","url":null,"abstract":"<p><p>Malaria remains one of the most devastating infectious diseases worldwide, predominantly caused by Plasmodium falciparum. Although the RTS,S and R21 vaccines have demonstrated partial efficacy, durable and broad protection across multiple parasite life stages remains an unmet need. Here, we report the development of a lipid-polyplex (LPP)-formulated mRNA vaccine platform targeting both the pre-erythrocytic and blood stages of P. falciparum. We designed mRNA constructs encoding the circumsporozoite protein (PfCSP) and the reticulocyte-binding protein homolog 5 (PfRH5), delivered either individually or as dual-antigen tandem forms. The optimized construct, RH5-T2A-CSP (Mal05), exhibited efficient antigen expression and elicited high-titer, durable antibodies capable of inhibiting sporozoite invasion and erythrocytic growth in vitro. In murine models, Mal05 induced robust Th1-biased CD4⁺ and CD8⁺ T-cell responses and conferred 100% sterile protection against challenge with transgenic Plasmodium berghei expressing PfCSP. Collectively, these findings demonstrate that dual-antigen mRNA-LPP vaccination can establish a potent, multistage immunological barrier by integrating neutralizing antibody activity with strong cellular immunity. Mal05 therefore represents a promising next-generation vaccine candidate with the potential to achieve both pre-erythrocytic and blood-stage protection. More broadly, this work highlights the potential of LPP-based mRNA technology for developing multistage vaccines against complex parasitic pathogens.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2983-2995"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148262719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clemastine alleviates cognitive dysfunction after SAH by targeting neuronal CNTN1 to regulate the ADA-adenosine pathway.","authors":"Long-Xiang Li, Bo-Yang Wei, Lei Jin, Yu Wu, Ze-Yu Yang, Can Li, Jia-Ming Zhou, Yu Song, Wen-Zhi Gong, Yuan-Hao Ou-Yang, Hao Huang, Xin Feng, Shen-Quan Guo, Wen-Ping Cheng, Ran Li, Shu-Yin Liang, Shi-Xing Su, Fa Jin, Xin Zhang, Yan-Chao Liu, Chuan-Zhi Duan, Wen-Chao Liu, Xi-Feng Li","doi":"10.1038/s41401-026-01852-3","DOIUrl":"10.1038/s41401-026-01852-3","url":null,"abstract":"<p><p>Demyelination following subarachnoid hemorrhage (SAH) is an important cause of cognitive impairment in patients. However, its underlying mechanisms remain unclear. This study aimed to elucidate the molecular basis of SAH-related demyelination and identify potential treatments. Contactin-1 (CNTN1) levels in the cerebrospinal fluid were significantly decreased in patients following SAH. Higher levels of CNTN1 expression correlated positively with Montreal Cognitive Assessment (MoCA) scores. However, whether and in which specific cell types CNTN1 expression is downregulated in the SAH brain parenchyma remains unknown. Our single-cell RNA sequencing revealed that Cntn1 was downregulated specifically in neurons, but not in oligodendrocytes. Then knockdown of Cntn1 in neurons via adeno-associated virus (AAV) significantly exacerbated cognitive impairment in mice with SAH. To investigate the mechanisms by which CNTN1 downregulation contributes to cognitive impairment, we performed transcriptome sequencing. This analysis revealed a significant decline in Ada, Plp1, and Mbp following CNTN1 knockdown in neurons. We therefore hypothesized that CNTN1 regulates neuronal ADA and existence of CNTN1-ADA-ADORA2B signaling axis. Through this axis, downregulation of CNTN1 after SAH might lead to demyelination. To validate our hypothesis, we overexpressed Cntn1 in murine neurons using AAV. Results demonstrated that Cntn1 overexpression effectively improved SAH-induced cognitive dysfunction, which can be blocked by ADA enzyme inhibitor. Furthermore, clemastine administration significantly attenuated cognitive impairment following SAH, by mitigating demyelination. Collectively, our results identify neuronal CNTN1 as a critical regulator. Its downregulation exacerbates demyelination through ADA after SAH. Importantly, clemastine might be potential drug used in SAH patients.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2862-2878"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic cannabinoid receptor agonists inhibit the cardiac voltage-gated potassium channel hERG.","authors":"Nina E Ottosson, Damon J A Frampton, Tanadet Pipatpolkai, Caitlyn Norman, Urban Karlsson, Amaia Jauregi-Miguel, Maryke Venter, Akshay Sridhar, H Peter Larsson, Henrik Gréen, Sara I Liin","doi":"10.1038/s41401-026-01876-9","DOIUrl":"10.1038/s41401-026-01876-9","url":null,"abstract":"<p><p>Synthetic cannabinoid receptor agonists (SCRAs) are a large group of structurally diverse designer drugs (analogues of controlled substances) associated with intense and sometimes fatal intoxication. Cardiac symptoms, including tachycardia and arrhythmia, are common consequences of SCRA consumption. However, little is known about the mechanisms through which SCRAs may perturb cardiac rhythm. Here, we used electrophysiological techniques to screen 36 SCRAs on two ion channels responsible for cardiomyocyte repolarization, hERG (also called K_V11.1) and K_V7.1/KCNE1. We report that the majority of tested SCRAs inhibited hERG, primarily by reducing channel conductance, and some also inhibited K_V7.1/KCNE1. In silico data suggest that SCRAs may use both a known drug binding site in the central cavity of the hERG channel, shared by established hERG blockers like astemizole, and a recently identified side pocket site. Experimental and in silico data suggest SCRA structural features associated with prominent inhibitory effects on hERG, with chemical moieties allowing bond formation and/or the ability to fit into binding sites being important. Structure-activity relationships (SAR) for SCRA effects on hERG, K_V7.1/KCNE1 and the cannabinoid receptor 1 (CB₁) varied, demonstrating the need to assess SCRA effects on multiple potential targets. In conclusion, we found SCRAs to be inhibitors of cardiac voltage-gated potassium channels important for cardiomyocyte repolarization, highlighting the importance of more extensive investigation of SCRAs on cardiac function.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2940-2954"},"PeriodicalIF":10.4,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Cardio-Onco-Immune Axis: immunopathological mechanisms in the cardiac microenvironment of checkpoint inhibitor-induced myocarditis.","authors":"Lian-Ke Liang, Qi Ye, Ji-Liang Li, Long-Ying Shi, Si-Ping Wang, Wei-Jie Liang, Ai-Lan Chen, Guo-Shuai Feng","doi":"10.1038/s41401-026-01947-x","DOIUrl":"https://doi.org/10.1038/s41401-026-01947-x","url":null,"abstract":"<p><p>The use of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, greatly improving patient survival rates. However, immune-related adverse events (irAEs), particularly immune checkpoint inhibitor-induced myocarditis (ICI myocarditis), have emerged as major concerns. These events are often fatal and present complex clinical challenges. Employing the Cardio-Onco-Immune Axis framework, this review systematically integrates recent mechanistic advances with the epidemiology, clinical manifestations, diagnosis, and treatment strategies, organizing the pathogenesis into three chronological phases. Phase 1-tumor antigen priming-involves thymic escape of cardiac-specific T cells followed by tumor-driven expansion of this self-reactive repertoire. Phase 2-systemic immune disinhibition-is triggered by ICI therapy, which impairs regulatory T cell (Treg)-mediated suppression and releases checkpoint inhibition, converting the primed pool into activated effector T cells. Phase 3-cardiac microenvironmental amplification-is driven by a multicellular inflammatory network within the myocardium that converts limited inflammation into progressive, often fulminant myocardial injury. The review also outlines future research avenues aimed at improving diagnostic techniques, discovering new biomarkers, and developing targeted interventions for immune pathways. By elucidating the mechanisms behind ICI myocarditis, this review aims to lay the foundation for risk stratification models, facilitating earlier detection and more precise treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}