Acta Pharmacologica Sinica最新文献

{"title":"Metabolic checkpoint blockade of IL4I1 by ZY-MY-111 reactivates CD8⁺ T cell immunity and suppresses tumor growth.","authors":"Ju-Fei Li, Hao Wang, Ling Kang, Cheng-Cheng Xu, Yuan-Chun Liu, Zi-Xuan Li, Shao-Hao Lin, Ming-Zhi Wang, Xiao-Min Xu, Pei-Pei Wang, Wan-Chao Yin, Yu-Bo Zhou, Yu Zhou, Jia Li","doi":"10.1038/s41401-026-01843-4","DOIUrl":"10.1038/s41401-026-01843-4","url":null,"abstract":"<p><p>Metabolic hijacking of tryptophan (Trp) via the IL4I1-AHR axis is a pivotal immune evasion mechanism in cancers, yet therapeutic strategies to disrupt this pathway remain unexplored. Here, we report the identification of ZY-MY-111, a selective small-molecule inhibitor of interleukin-4-induced-1 (IL4I1), through an in-house compound library screening and structural optimization. ZY-MY-111 exhibits potency (IC₅₀ = 1.86 ± 0.13 μM) in blocking IL4I1-mediated oxidative deamination. Mechanistically, ZY-MY-111 acts as a mixed-type inhibitor, competitively occupying the catalytic pocket of IL4I1 and disrupting Trp-AHR signaling in cells. Functionally, ZY-MY-111 promotes T cell proliferation, enhancing immune responses against the tumor cells. In syngeneic tumor models, ZY-MY-111 achieved 49% tumor growth inhibition in CT26 colon carcinoma (P < 0.001) and 56% tumor growth inhibition in A20 lymphoma (P < 0.001) by remodeling the immunosuppressive microenvironment: increasing CD8⁺/CD4⁺ T cell ratios, reducing myeloid-derived suppressor cells (MDSCs, 59% decrease), and enhancing effector memory T cell infiltration. Our findings position IL4I1 inhibition as a potential strategy to restore anti-tumor immunity.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2682-2691"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148196928","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":"S1UTRSP5, a short restructured RNA from SLIT1 3'UTR, mitigates mouse cardiac remodeling via enhancing SlRT1 activity.","authors":"Jin-Feng Su, Tao Ou, Xiao-Yao Liu, Xue-Min Su, Ya Wang, Yi-Hong Wen, Yuan Gao, Ruo-Han Li, Lu-Fang Huang, Chuan-Meng Zhou, Heng-Li Zhao, Jie-Ning Zhu, Ning Ma, Xi-Long Zheng, Yu-Peng Liu, Jin-Dong Xu, Hui Li, Xian-Hong Fang, Zhi-Xin Shan","doi":"10.1038/s41401-026-01859-w","DOIUrl":"10.1038/s41401-026-01859-w","url":null,"abstract":"<p><p>The 3' untranslated regions (3'UTRs) have been known to regulate mRNA location, stability, and translation. 3'UTR length regulation is involved in the pathogenesis of cardiac dysfunction; however, more about the roles of 3'UTRs in cardiac remodeling remains elusive. In this study, we found slit guidance ligand 1 (SLIT1) 3'UTR with 3074 nt in length, which was 10-fold higher than SLIT1 coding sequence (CDS), was significantly decreased in the myocardium of patients with heart failure (HF) (n = 40) in comparison with healthy organ donors (n=17). We revealed that SLIT1 3'UTR and the 1526 nt fragment of SLIT1 3'UTR (FS1UTR) mainly and specifically combined miR-34a-5p, and improved cardiac remodeling through the miR-34a-5p/SIRT1 axis independently of Slit1 expression. Furthermore, a 260 nt restructured RNA derived from FS1UTR, S1UTRSP5, which contains 5 binding sites of miR-34a-5p seed sequence, alleviated cardiac remodeling in vitro and in vivo. We demonstrated that S1UTRSP5 blocked the function of miR-34a-5p and activated the SIRT1-PGC-1α-Nrf2 axis in cardiomyocytes, and promoted the SIRT1/Smad3 signal in cardiac fibroblasts and the SIRT1-eNOS-VEGFA axis in endothelial cells, collectively contributing to the amelioration of cardiac remodeling. These results provide new insights into the development of S1UTRSP5 as a novel inhibitor of miR-34a-5p for cardiac remodeling and HF. The human SLIT1 3'UTR or FS1UTR combines miR-34a-5p to increase SIRT1 level in CMs, CFs and ECs. Notably, S1UTRSP5, a 260-nt stable RNA derived from SLIT1 3'UTR, efficiently sponged miR-34a-5p to activate SIRT1-PGC-1α-Nrf2 pathway in CMs, and to promote SIRT1/Smad3 signal in CFs and the SIRT1-eNOS-VEGFA pathway in ECs, collectively contributing to amelioration of cardiac remodeling.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2525-2538"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148222425","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":"CCS facilitates the progression of ovarian cancer by suppressing ferroptotic cell death via the modulation of p53-mediated expression of SLC7A11 and GPX4.","authors":"Qi Yan, Ming-Ming Sun, Xin-Ru Zhai, Hong-Kai Chang, Xin-Yue Geng, Xiao-Bo Zhai, Chen-Xin Yang, Yan-Ping Li, Tao Wang, Jian-Guo Zhao, Tao He, Chang-Liang Shan, Shuai Zhang","doi":"10.1038/s41401-026-01816-7","DOIUrl":"10.1038/s41401-026-01816-7","url":null,"abstract":"<p><p>Ovarian cancer is the most prevalent and deadly gynecological malignancy worldwide, with a 5-year overall survival rate of only 10%-40% for patients with advanced disease. Copper chaperone for superoxide dismutase 1 (CCS) is a metallochaperone that plays a multifaceted role in the maturation of copper and displays aberrant expression levels and functions in cancer. Ferroptosis, a new form of cell death resulting from iron-dependent lipid peroxidation, is closely related to cancer. However, whether CCS regulates ferroptosis in ovarian cancer is unknown, and its underlying mechanisms have not been reported. Here, we report that highly expressed CCS contributes to ovarian cancer tumor growth. Moreover, suppressing CCS induced ferroptosis in ovarian cancer cells and increased their sensitivity to ferroptosis inducers. Mechanistically, high CCS expression was found to reduce intracellular copper ion levels and increase Solute Carrier Family 7 Member 11 (SLC7A11) or Glutathione Peroxidase 4 (GPX4) expression by increasing p53 ubiquitination, thus affecting ferroptosis. Additionally, DC_AC50, a small-molecule inhibitor of CCS that targets its copper transport interface, regulates ferroptosis and ovarian cancer growth. Analysis of clinical data revealed a positive correlation between high CCS expression and high SLC7A11 and GPX4 expression in ovarian cancer patients. In summary, our study reveals that CCS protects ovarian cancer cells from ferroptosis by promoting SLC7A11 and GPX4 expression in a p53-dependent manner.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2638-2652"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961810","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":"G protein-coupled receptor 75 mediates depression-like behaviors and HPA axis hyperactivity through an excitatory arcuate-paraventricular nucleus circuit.","authors":"Hao Wang, Yi-Hong Wei, An-Qi Gao, Juan-Juan Guo, Xin Ding, Jing-Jing Yang, Zi-Ru Wang, Jun-Cheng Da, Yue Kang, Jian-Hua Ding, Yi Fan, Ming Lu, Li Zhang, Gang Hu","doi":"10.1038/s41401-026-01824-7","DOIUrl":"10.1038/s41401-026-01824-7","url":null,"abstract":"<p><p>Metabolic dysregulation is a core pathological feature of and a major risk factor for depression. In this study, the role of G protein-coupled receptor 75 (GPR75), a brain-enriched metabolic sensor, in the pathogenesis of depression was explored and its potential role as a therapeutic target was evaluated. In chronic social defeat stress (CSDS) models, GPR75 expression was specifically upregulated in the arcuate nucleus glutamatergic (ARC^Vglut2) neurons of susceptible mice, a finding corroborated by analyses of postmortem brains from patients with depression. Conditional (GPR75-cKO) or local (GPR75-lKO) genetic knockout of GPR75 in these neurons resulted in robust antidepressant-like effects, alleviation of depression-like behaviors, and normalization of the hypothalamic-pituitary-adrenal (HPA) axis function. Pharmacological inhibition of GPR75 with an antagonist (AAA) elicited similar antidepressant-like effects. Conversely, overexpression or activation of GPR75 in ARC^Vglut2 neurons promoted depression-like behaviors in naïve mice. Mechanistically, GPR75 signaling acts through the Gαq-PLCβ-IP3R1 pathway to enhance Ca²⁺ release from the endoplasmic reticulum and increase neuronal excitability. This facilitates glutamate release in the paraventricular nucleus (PVN), resulting in HPA axis activation. Chemogenetic inhibition of ARC^Vglut2 neurons or the ARC^Vglut2-PVN circuit replicated the antidepressant-like effects of GPR75 ablation, whereas their activation abolished these benefits. These findings establish GPR75 expression in ARC^Vglut2 neurons as a critical mediator of depression and a potential target for novel antidepressants.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2377-2391"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986214","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 multilevel exploration test, a novel paradigm to measure exploratory behavior in depression animal models and the involvement of the PL-ZI circuit.","authors":"Jun-Nan Xu, Jing-Ting Li, Ru-Xia Xu, Yun-Feng Wang, He-Wei Gao, Hao-Tian He, Han Guo, Yu Liang, Yong-Dan Zhu, Xiao-Wen Li, Jian-Ming Yang, Xiao-Ming Li, Yi-Hua Chen, Tian-Ming Gao","doi":"10.1038/s41401-026-01812-x","DOIUrl":"10.1038/s41401-026-01812-x","url":null,"abstract":"<p><p>Diminished drive is one of the core symptoms of major depressive disorder (MDD) diagnosis, yet its underlying neural mechanisms remain elusive, primarily due to a lack of appropriate animal models. We developed a novel Multilevel Exploration Test (MET) apparatus to evaluate exploratory behavior, which is captured as a dynamic, stage-dependent process involving \"search\", \"attend/investigate\", and \"approach\" phases. We employed fiber photometry to measure real-time dopamine dynamics in the nucleus accumbens. We further combined cFos staining and neural circuit tracing to identify relevant brain regions and circuits, and employed chemogenetics to selectively modulate prelimbic cortex (PL) inputs to zona incerta (ZI). The MET tests were conducted across five depression models, with ketamine administration to evaluate rescue effects. Machine learning algorithms were utilized to analyze MET data and predict individual emotional states (normal, anxiety-like, depression-like). Here, we developed a novel paradigm to assess exploratory behavior, which demonstrates etiological validity, face validity and predictive validity. Depressed mice exhibited reduced motivation for exploration in this paradigm, while stimulation of the PL-ZI circuit not only restored exploratory deficits but also alleviated other depression-like behaviors in these mice. Furthermore, we established a machine learning-based model to predict individual animals' emotional states by integrating data from the new paradigm, achieving a prediction accuracy of over 92%. The MET provides a functional, high-throughput paradigm for dissecting motivation-related pathology. It facilitates the assessment of depressive-like behaviors, enables the prediction of emotional states, and supports the discovery of novel targets for antidepressant development.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2409-2420"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969452","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":"METTL16 S-glutathionylation-triggered RNA m⁶A modification of IGF2BP3 inhibits CFTR expression and promotes chemoresistance in colorectal cancer.","authors":"Lu Xu, Yan Ma, Wang Yao, Ya-Ju Qiu, Chao Xu, Fang-Yue Xu, Zhi-Miao Zou, Wu-Min Dai, Wan-Gang Gong, De-Ning Ma, Xiao-Wan Chen, Wen-Kai Ye, Yi-Yun Huang, Hai-Tao Chen, Lue Hong, Jia-Ping Mo, Jian-Guo Feng, En-Yan Yu, Wei Chen, Yu-Hua Zhang, Qing-Hua Yao, Xia Li","doi":"10.1038/s41401-026-01821-w","DOIUrl":"10.1038/s41401-026-01821-w","url":null,"abstract":"<p><p>5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC) involves oxidative stress mechanisms, but the role of epitranscriptomic regulation remains unclear. This study investigates how oxidative post-translational modifications of the N6-methyladenosine (m⁶A) methyltransferase METTL16 contribute to 5-FU resistance. Parental (HCT8, HCT15) and 5-FU-resistant CRC cells were compared using redox proteomics, m⁶A-seq, RNA-seq, and functional assays. METTL16 S-glutathionylation was assessed via streptavidin pulldown and mass spectrometry. IGF2BP3's role was validated through knockdown/overexpression, patient-derived organoids (PDOs), and xenograft models. Clinical relevance was evaluated in 112 CRC patient tissues and data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Drug synergy was tested using isoliquiritigenin (ISO) combined with 5-FU. Resistant cells exhibited elevated global protein S-glutathionylation and reduced m⁶A RNA methylation. METTL16 underwent site-specific S-glutathionylation at Cys548, leading to its degradation and subsequent m⁶A loss. Integrative omics identified IGF2BP3 as a key METTL16 target: reduced m⁶A on IGF2BP3 mRNA enhanced its nuclear export, splicing, and overexpression. IGF2BP3 knockdown sensitized resistant cells to 5-FU in vitro and in vivo, while overexpression conferred resistance. Mechanistically, IGF2BP3 destabilized CFTR mRNA (an ABC transporter), reducing 5-FU uptake. Clinically, high IGF2BP3 correlated with poor survival and 5-FU resistance in CRC patients. Targeting IGF2BP3 with ISO synergized with 5-FU, overcoming resistance in cells and xenografts. Oxidative stress-induced METTL16 S-glutathionylation drives 5-FU resistance by reducing m⁶A modification, enabling IGF2BP3 overexpression and CFTR suppression. IGF2BP3 is a biomarker of clinical resistance, and its targeting with ISO represents a promising combinatorial strategy to restore 5-FU efficacy in CRC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2619-2637"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979999","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":"Astrocytic adrenergic α2 receptor contributes to the mechanisms underlying the circadian rhythmicity of seizure susceptibility.","authors":"Cong Wang, Ping-Chuan Yuan, Qian Sun, Michael Lazarus, Wei-Min Qu, Zhi-Li Huang, Feng-Fei Ding","doi":"10.1038/s41401-026-01833-6","DOIUrl":"10.1038/s41401-026-01833-6","url":null,"abstract":"<p><p>Circadian rhythmicity in seizure susceptibility has been documented in patients with epilepsy. We established a chemogenetic epilepsy model induced using Gq-coupled designer receptors exclusively activated by designer drugs to examine the mechanisms underlying the circadian rhythmicity of seizure susceptibility. Intraperitoneal administration of clozapine N-oxide (CNO) induced dose-dependent seizure behaviors characteristic of mild (Racine scale III or less) and severe (Racine scale IV-V) seizures. CNO at a dose of 0.5 mg/kg elicited significantly more severe seizures during the light phase (Zeitgeber time 3 [ZT 3]) compared with the dark phase (ZT 15). Chemogenetic activation of the Gi instead of the Gq pathway in hippocampal astrocytes suppressed the number of mild seizures exclusively during the light phase. Astrocyte-specific knockdown of adrenergic α2 but not α1 or β receptors exacerbated seizure susceptibility specifically in the light phase, an effect partially reversed by administration of 0.2 mg/kg of dexmedetomidine, an adrenergic α2 agonist. The administration of atipamezole, an α2 antagonist, significantly upregulated norepinephrine-induced lactate production in both intra- and extra-cellularly cultured astrocytes. Supplementation with medium-chain fatty acids in epileptic mice rescued astrocytic α2 receptor knockdown-induced seizure exacerbation, which produce blood-brain-barrier-permeable ketone bodies that likely balance the pro-epileptic lactate burden. Taken together, these findings suggest that astrocytic adrenergic α2 signaling at least partly mediates circadian rhythmicity in seizure susceptibility.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2467-2478"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025380","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":"TGF-β2 signaling promotes cardiac fibrosis in arrhythmogenic right ventricular cardiomyopathy mediated by DSC2 deficiency.","authors":"Chen-Xing Huang, Ke-Jia Jin, Lan-Qing Xiang, Zhuo-Xin Lv, Ying Wang, Jian-Guo Jia, Fei-Zhen Wu, Yi-Zhun Zhu, Yun-Zeng Zou, Yu-Xiang Dai, Hui Gong","doi":"10.1038/s41401-026-01846-1","DOIUrl":"10.1038/s41401-026-01846-1","url":null,"abstract":"<p><p>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and an increased risk of sudden cardiac death. Pathogenic variants of desmosomal genes have been implicated in ARVC pathogenesis and may disrupt desmosomal protein function. However, whether and how desmosomal protein dysfunction directly activates cardiac fibroblasts to mediate fibrosis remains poorly understood. To address this, we combined genetic analysis with in vivo and cellular models to investigate the role of desmosomal dysfunction in cardiac fibrosis. The systematic genetic analysis revealed that desmosomal gene variants are predominant in ARVC, accounting for 67.4% of cases in cohort studies and 96.1% of pathogenic variants in ClinVar. We used desmocollin-2 (DSC2) knockout mice to recapitulate key features of ARVC, including right ventricular fibrosis, enlargement, and dysfunction. In vitro, DSC2 deficiency directly activates cardiac fibroblasts, resulting in increased cell proliferation, migration, and fibrosis marker expression. Further analysis identified transforming growth factor beta-2 (TGF-β2) as a critical signaling mediator in cardiac fibrosis of DSC2 deficiency-mediated ARVC. Mechanistically, DSC2 deficiency upregulated transcription factor 7 (TCF7) expression, promoting its binding to TGF-β2 promoter regions to enhance TGF-β2 transcription in cardiac fibroblasts. Pharmacological inhibition of TGF-β2 with pirfenidone (PFD) effectively attenuated cardiac fibrosis and improved right ventricular function in DSC2-deficient hearts. The results of the present study identified DSC2 deficiency-mediated TCF7-TGF-β2 signaling in cardiac fibroblasts, which contributed to ARVC development. Thus, targeting TGF-β2 signaling may be a promising therapeutic strategy for desmosome gene mutation-related ARVC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2510-2524"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343718","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":"Stevioside promotes hepatocyte proliferation via YAP signaling in cholestatic disease.","authors":"Wei Jiang, Xu-Yi Fang, Yi-Meng Sun, Meng-Yuan Xu, Xin Han, Shuo-Jun Yan, Xu Liu, Ya-Yun Liu, Xian Zeng, Wen-Qiang Lai, Jin-Quan Huang, Bin Zhou, Xiao-Wei Meng, Yong-Xu Zhao, Yan Li","doi":"10.1038/s41401-026-01914-6","DOIUrl":"https://doi.org/10.1038/s41401-026-01914-6","url":null,"abstract":"<p><p>Stevioside, a natural glycoside with diverse bioactivities, holds therapeutic potential in liver diseases, but its role in cholestatic liver repair remains largely unexplored. This study investigates the regenerative efficacy and underlying mechanisms of stevioside in bile duct ligation (BDL)-induced cholestatic liver injury. A combined pre- and post-treatment regimen of stevioside (90 mg/kg) robustly mitigated hepatic damage, evidenced by reduced necrosis, suppressed inflammation, attenuated ductular reaction, and improved hepatic function. Notably, stevioside significantly stimulated hepatocyte proliferation, as indicated by increased liver-to-body weight ratios, upregulation of cell-cycle regulators (Ccnd1, Ccna2), and transcriptomic enrichment of proliferation-related pathways. Utilizing the genetic proliferation tracing system (ProTracer), we further demonstrated that stevioside preferentially promotes the regeneration of periportal (Zone 1) and midzonal (Zone 2) hepatocytes. Conversely, it constrained the expansion of biliary epithelial cells and immune cells, thereby collectively alleviating pathological ductular reaction and inflammatory infiltration. Mechanistically, stevioside activated YAP signaling in hepatocytes and remodeled bile acid metabolism, together creating a favorable microenvironment for liver regeneration. Furthermore, stevioside exhibited a favorable safety profile with no detectable hepatotoxicity, fibrosis, or tumorigenic risk under the experimental conditions. Our findings establish that stevioside repairs cholestatic injury by directly driving region-restricted hepatocyte proliferation via YAP signaling, highlighting its potential as a mechanistically innovative candidate for the treatment of cholestatic liver diseases.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148862932","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}

{"title":"The cardiac protective human circular RNA circKLHL20_009 sponges miR-31-5p to ameliorate myocardial hypertrophy and fibrosis through suppressing β-catenin signaling.","authors":"Yi-Hong Wen, Jia-Xue Jiang, Wen-Yan Dong, Jing Guo, Qing-Yue Hu, Xiao-Yao Liu, Zhen-Zhen Yang, Lu-Fang Huang, Jie-Ning Zhu, Meng-Zhen Zhang, Xi-Pei Wang, Yu-Peng Liu, Ning Ma, Xi-Long Zheng, Wen-Qian Cai, Jin-Dong Xu, Xian-Hong Fang, Zhi-Xin Shan","doi":"10.1038/s41401-026-01912-8","DOIUrl":"https://doi.org/10.1038/s41401-026-01912-8","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) participate in the process of pathological cardiac remodeling; however, the roles of dysregulated circRNAs remain unclear. In this study, we revealed that the expression of the circRNA circKLHL20_009 was significantly upregulated in the myocardium of patients with heart failure (HF) and in human cardiomyocytes treated with angiotensin II (Ang II). In vivo, the cardiac-specific expression of circKLHL20_009 ameliorated transverse aortic constriction (TAC) surgery-induced cardiac remodeling in mice. The enforced expression of circKLHL20_009 abolished Ang II-induced cardiomyocyte hypertrophy and the fibrotic phenotypes of cardiac fibroblasts, and it mitigated cryoinjury-induced cardiac organ fibrosis. Mechanistically, circKLHL20_009 specifically sponged miR-31-5p to increase Dickkopf-1 (DKK1) expression and inactivate β-catenin signaling in an LRP6-dependent manner, thereby decreasing the expression of genes related to cardiac hypertrophy and fibrosis. Notably, we designed and demonstrated that an artificial circRNA sponge, circSPmiR31, which contains six repeats of the miR-31-5p binding site, effectively mitigated cardiac hypertrophy and fibrosis by suppressing miR-31-5p binding to Dkk1 mRNA. These results provide new insights into the development of therapeutics for cardiac remodeling based on a circularized RNA sponge targeting miR-31-5p. The human circKLHL20_009 ameliorates cardiac remodeling through the DKK1-LRP6/β-catenin axis via sponging miR-31-5p. The artificial circRNA sponge, circSPmiR31, effectively mitigates cardiac hypertrophy and fibrosis through inhibiting miR-31-5p binding to Dkk1 mRNA, holding a therapeutic promise in cardiac hypertrophy and fibrosis, and HF.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811425","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}