Acta Pharmacologica Sinica最新文献

{"title":"Humanized dual-targeting antibody-drug conjugates specific to MET and RON receptors as a pharmaceutical strategy for the treatment of cancers exhibiting phenotypic heterogeneity.","authors":"Minghai Wang, Qi Ma, Sreedhar Reddy Suthe, Rachel E Hudson, Jing-Ying Pan, Constantinos Mikelis, Miao-Jin Zhu, Zhi-Gang Wu, Dan-Rong Shi, Hang-Ping Yao","doi":"10.1038/s41401-024-01458-7","DOIUrl":"https://doi.org/10.1038/s41401-024-01458-7","url":null,"abstract":"<p><p>Cancer heterogeneity, characterized by diverse populations of tumorigenic cells, involves the occurrence of differential phenotypes with variable expressions of receptor tyrosine kinases. Aberrant expressions of mesenchymal-epithelial transition (MET) and recepteur d'origine nantais (RON) receptors contribute to the phenotypic heterogeneity of cancer cells, which poses a major therapeutic challenge. This study aims to develop a dual-targeting antibody-drug conjugate (ADC) that can act against both MET and RON for treating cancers with high phenotypic heterogeneity. Through immunohistochemical staining, we show that MET and RON expressions are highly heterogeneous with differential combinations in more than 40% of pancreatic and triple-negative breast cancer cases. This expressional heterogeneity provides the rationale to target both receptors for cancer therapy. A humanized bispecific monoclonal antibody specific to both MET and RON (PCMbs-MR) is generated through IgG recombination using monoclonal antibody sequences specific to MET and RON, respectively. Monomethyl auristatin E is conjugated to PCMbs-MR to generate a dual-targeting ADC (PCMdt-MMAE), with a drug-to-antibody ratio of 4:1. Various cancer cell lines were used to determine PCMdt-MMAE-mediated biological activities. The efficacy of PCMdt-MMAE in vivo is evaluated using multiple xenograft tumor models. PCMdt-MMAE shows a favorable pharmacokinetic profile, with a maximum tolerated dose of ~30 mg/kg in mice. Toxicological studies using Sprague-Dawley rats reveal that PCMdt-MMAE is relatively safe with slight-to-moderate, temporary, and reversible adverse events. Functionally, PCMdt-MMAE induces a robust internalization of both MET and RON and causes a large-scale cell death in cancer cell lines exhibiting MET and RON heterogeneous co-expressions. Both in vitro and in vivo studies demonstrate that the dual-targeting approach in the form of an ADC is highly effective with a long-lasting effect against tumors exhibiting MET/RON heterogeneous phenotypes. Hence, we can suggest that a dual-targeting ADC specific to both MET and RON can be employed as a novel therapeutic strategy for tumors with expressional phenotypic heterogeneity.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997973","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":"BE-43547A₂ exerts hypoxia-selective inhibition on human pancreatic cancer cells through targeting eEF1A1 and disrupting its association with FoxO1.","authors":"Can Liu, Can Liu, Guang-Ju Liu, Meng-Meng Wang, Yan Jiao, Yuan-Jun Sun, Hui Guo, Liang Wang, Ya-Xin Lu, Yue Chen, Ya-Hui Ding","doi":"10.1038/s41401-024-01461-y","DOIUrl":"https://doi.org/10.1038/s41401-024-01461-y","url":null,"abstract":"<p><p>Hypoxia is a key feature of the tumor microenvironment that leads to the failure of many chemotherapies and induces more aggressive and resistant cancer phenotypes. Up to date, there are very few compounds and treatments that can target hypoxia. BE-43547A₂ from Streptomyces sp. was one of the most hypoxia-selective compounds against PANC-1, MCF-7, and K562 cell lines. In this study, we investigated the molecular mechanism underlying the hypoxia selectivity of BE-43547A₂ in human pancreatic cancer cells. We showed that BE-43547A₂ displayed hypoxia-selective cytotoxicity in five pancreatic cancer cells (PANC-1, Capan-2, MIA PaCa-2, AsPC-1, and PaTu8988T) with IC₅₀ values under hypoxia considerably lower than those under normoxia. We demonstrated that BE-43547A₂ is directly bound to eEF1A1 protein in PaTu8988T cells under hypoxia. Furthermore, we revealed that hypoxia significantly elevated the expression levels of HIF1α, FoxO1, and eEF1A1 in the five pancreatic cancer cells; eEF1A1 interacted with FoxO1 in the cytoplasm, which was disrupted by BE-43547A₂ followed by the nuclear translocation of FoxO1 and ultimate inhibition of JAK/STAT3 signaling pathway under hypoxia. This study reveals that BE-43547A₂, targeting eEF1A1, disrupts its interaction with FoxO1 in human pancreatic cancer cells under hypoxia. This compound could serve as a potential hypoxia-selective therapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998037","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":"Dehydrocorydaline maintains the vascular smooth muscle cell contractile phenotype by upregulating Spta1.","authors":"Yuan-Ye Dang, Cui Chen, Qiu-Fen Wei, Li-Feng Gao, Shun-Chi Zhang, Yong-Xian Li, Xiao-Yan Dai","doi":"10.1038/s41401-024-01464-9","DOIUrl":"https://doi.org/10.1038/s41401-024-01464-9","url":null,"abstract":"<p><p>Vascular smooth muscle cell (VSMC) phenotypic switching plays a crucial role in the initiation and progression of atherosclerosis. Dehydrocorydaline (DHC), a major active component of the traditional Chinese herbal medicine Rhizoma Corydalis, exhibits diverse pharmacological effects. However, its impact on VSMCs remains largely unknown. This study aims to investigate the effects and underlying mechanisms of DHC in phenotypic switching of VSMCs. Our study revealed that DHC increased the mRNA and protein levels of rat VSMC contractile phenotype markers, such as calponin 1 (Cnn1), myosin heavy chain (Myh11, SM-MHC), smooth muscle 22α (Sm22α), and alpha-smooth muscle actin (Acta2, α-SMA) in a time- and dose-dependent manner. Additionally, DHC inhibited platelet-derived growth factor-BB-induced VSMC proliferation and migration. In Apoe^-/- mice, DHC treatment resulted in reduced carotid plaque areas and macrophage infiltration, along with increased contractile phenotype marker expression. RNA sequencing analysis revealed a significant upregulation of spectrin alpha, erythrocytic 1 (Spta1) in DHC-treated rat VSMCs. Strikingly, Spta1 knockdown effectively negated the increase in contractile phenotype marker expression in VSMCs that was initially prompted by DHC. Therefore, DHC preserves the VSMC contractile phenotype through Spta1, thereby attenuating carotid artery atherosclerotic plaques in Apoe^-/- mice. This study provides evidence supporting the potential use of Chinese herbal medicines, particularly those containing DHC such as Rhizoma Corydalis, in the treatment of atherosclerotic cardiovascular disease, thus expanding the clinical application of such herbal remedies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998017","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":"JOSD2 inhibits angiotensin II-induced vascular remodeling by deubiquitinating and stabilizing SMAD7.","authors":"Si-Rui Shen, Zhu-Qi Huang, Yu-Die Yang, Ji-Bo Han, Zi-Min Fang, Yue Guan, Jia-Chen Xu, Ju-Lian Min, Yi Wang, Gao-Jun Wu, Zhong-Xiang Xiao, Wu Luo, Zhou-Qing Huang, Guang Liang","doi":"10.1038/s41401-024-01437-y","DOIUrl":"https://doi.org/10.1038/s41401-024-01437-y","url":null,"abstract":"<p><p>Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. In this study, we identified the deubiquitinating enzyme Josephin domain-containing protein 2 (JOSD2) as a protective factor and investigated its molecular mechanism in Ang II-induced vascular remodeling. First, we found that JOSD2 was upregulated in aortic smooth muscle cells, but not in endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by vascular smooth muscle cell (VSMC)-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated Ang II-induced fibrosis, proliferation, and migration VSMCs, while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to the TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in the TGFβ-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to remove the K48-linked ubiquitin chains from SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that the JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 may be a novel and potential therapeutic target for hypertensive vascular remodeling.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998101","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":"Identifying a non-conserved site for achieving allosteric covalent inhibition of CECR2.","authors":"Cai-Ling Tang, Yuan-Qing Li, Xi-Kun Du, Xiao-Xia Fang, Yi-Man Guang, Pei-Zhuo Li, Shuang Chen, Sheng-Yu Xue, Jia-Min Yu, Xiao-Yi Liu, Yi-Pan Luo, Lan-Xin Zhou, Cheng Luo, Huan Xiong, Zhong-Jie Liang, Hong Ding","doi":"10.1038/s41401-024-01452-z","DOIUrl":"https://doi.org/10.1038/s41401-024-01452-z","url":null,"abstract":"<p><p>The bromodomain (BRD) represents a highly conserved structural module that provides BRD proteins with fundamental functionality in modulating protein-protein interactions involved in diverse biological processes such as chromatin-mediated gene transcription, DNA recombination, replication and repair. Consequently, dysregulation of BRD proteins has been implicated in the pathogenesis of numerous human diseases. In recent years, considerable scientific endeavors have focused on unraveling the molecular mechanisms underlying BRDs and developing inhibitors that target these domains. While these inhibitors compete for binding with the acetylated lysine binding site of BRDs, achieving inhibition of BRD proteins via competitive pocket binding has proven challenging due to the conserved nature of these pockets. To address this limitation, the present study employed dynamic simulations for a comprehensive analysis, leading to the identification of a non-conserved pocket in CECR2 for achieving BRD family inhibition through allosteric modulation. Subsequently, the compound BAY 11-7085 was proven capable of covalently binding to C494 of this pocket after covalent docking and biological verification in vitro. The allosteric inhibition strategy of CECR2 was further verified by the structurally optimized compound LC-CE-7, which is an allosteric covalent CECR2 inhibitor with anti-cancer effects in MDA-MB-231 cells.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998100","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":"Peptidoglycan isolated from the fruit of Lycium barbarum alleviates liver fibrosis in mice by regulating the TGF-β/Smad7 signaling and gut microbiota.","authors":"Ying-Min Nie, Wan-Qi Zhou, Ting Niu, Meng-Fei Mao, Yu-Xue Zhan, Yun Li, Kai-Ping Wang, Mei-Xia Li, Kan Ding","doi":"10.1038/s41401-024-01454-x","DOIUrl":"https://doi.org/10.1038/s41401-024-01454-x","url":null,"abstract":"<p><p>The hepatoprotective effect of the fruit of Lycium barbarum has been documented in China over millennia. Lycium barbarum polysaccharides (LBPs) were the first macromolecules reported to mitigate liver fibrosis in carbon tetrachloride (CCl₄)-treated mice. Herein, a neutral peptidoglycan, named as LBPW, was extracted from the fruit of Lycium barbarum. In this study, we investigated the hepatoprotective mechanisms of LBPW. CCl₄-induced liver fibrosis mice were administered LBPW (50, 100, 200 mg ·kg^-1 ·d^-1, i.p.) or (100, 200, 300 mg· kg^-1 ·d^-1, i.g.) for 6 weeks. We showed that either i.p. or i.g. administration of LBPW dose-dependently attenuated liver damage and fibrosis in CCl₄-treated mice. Pharmacokinetic analysis showed that cyanine 5.5 amine (Cy5.5)-labeled LBPW (Cy5.5-LBPW) could be detected in the liver through i.p. and i.g. administration with i.g.-administered Cy5.5-LBPW mainly accumulating in the intestine. In TGF-β1-stimulated LX-2 cells as well as in the liver of CCl₄-treated mice, we demonstrated that LBPW significantly upregulated Smad7, a negative regulator of TGF-β/Smad signaling, to retard the activation of hepatic stellate cells (HSCs) and prevent liver fibrosis. On the other hand, LBPW significantly boosted the abundance of Akkermansia muciniphila (A. muciniphila) and fortified gut barrier function. We demonstrated that A. muciniphila might be responsible for the efficacy of LBPW since decreasing the abundance of this bacterium by antibiotics (Abs) blocked the effectiveness of LBPW. Overall, our results show that LBPW may exert the hepatoprotective effect via rebalancing TGF-β/Smad7 signaling and propagating gut commensal A. muciniphila, suggesting that LBPW could be leading components to be developed as new drug candidates or nutraceuticals against liver fibrosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998267","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":"Therapeutic potential and pharmacological mechanisms of Traditional Chinese Medicine in gout treatment.","authors":"Jing-Wen Guo, Guo-Qiang Lin, Xin-Yi Tang, Jia-Ying Yao, Chen-Guo Feng, Jian-Ping Zuo, Shi-Jun He","doi":"10.1038/s41401-024-01459-6","DOIUrl":"https://doi.org/10.1038/s41401-024-01459-6","url":null,"abstract":"<p><p>Gout is a systemic metabolic disorder caused by elevated uric acid (UA) levels, affecting over 1% of the population. The most common complication of gout is gouty arthritis (GA), characterized by swelling, pain or tenderness in peripheral joints or bursae, which can lead to the formation of tophi. At present, western medicines like colchicine, febuxostat and allopurinol are the primary treatment strategy to alleviate pain and prevent flare-ups in patients with GA, but they have significant side effects and increased mortality risks. Traditional Chinese medicine (TCM) has been utilized for thousands of years for the prevention and treatment of GA, demonstrating effective control over serum UA (SUA) levels with fewer side effects. Herein we summarized a total of 541 studies published from 2000 to 2023 in sources including PubMed, Web of Science, the Cochrane Library and Embase, highlighting the therapeutic potential of TCM in treating gout and GA, particularly in combination with modern medical strategies. This review focuses on TCM formulas, Chinese herbal extracts, and active compounds derived from TCM, providing an overview of recent clinical application and the pharmacological research based on animal models and cellular systems. Particularly, the current review categorized the clinical and experimental evidence into the strategies for improving hyperuricemia, decreasing the sudden onset of acute GA and retarding chronic GA progression, supplied further coherent reference and enlightenment for clinicians, investigators of natural product chemistry, researchers in TCM and pharmacology. We hope this article will inspire the development of novel formulas and molecular entities for the treatment of gout and GA.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998272","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":"Genome-wide CRISPR-Cas9 screening identifies ITGA8 responsible for abivertinib sensitivity in lung adenocarcinoma.","authors":"Xuan-Guang Li, Guang-Sheng Zhu, Pei-Jun Cao, Hua Huang, Yu-Hao Chen, Chen Chen, Pei-Jie Chen, Di Wu, Chen Ding, Zi-He Zhang, Rui-Hao Zhang, Zi-Xuan Hu, Wen-Hao Zhao, Ming-Hui Liu, Yong-Wen Li, Hong-Yu Liu, Jun Chen","doi":"10.1038/s41401-024-01451-0","DOIUrl":"https://doi.org/10.1038/s41401-024-01451-0","url":null,"abstract":"<p><p>The emergence of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the prognosis for lung cancer patients with EGFR-driven mutations. However, acquired resistance to EGFR-TKIs poses a significant challenge to the treatment. Overcoming the resistance has primarily focused on developing next-generation targeted therapies based on the molecular mechanisms of resistance or inhibiting the activation of bypass pathways to suppress or reverse the resistance. In this study we developed a novel approach by using CRISPR-Cas9 whole-genome library screening to identify the genes that enhance the sensitivity of lung adenocarcinoma cells to EGFR-TKIs. Through this screening, we revealed integrin subunit alpha 8 (ITGA8) as the key gene that enhanced sensitivity to abivertinib in lung adenocarcinoma. Notably, ITGA8 expression was significantly downregulated in lung adenocarcinoma tissues compared to adjacent normal tissues. Bioinformatics analyses revealed that ITGA8 was positively correlated with the sensitivity of lung adenocarcinoma to abivertinib. We showed that knockdown of ITGA8 significantly enhanced the proliferation, migration and invasion of H1975 cells. Conversely, overexpression of ITGA8 reduced the proliferation migration and invasion of H1975/ABIR cells. Furthermore, we demonstrated that ITGA8 sensitized lung adenocarcinoma cells to EGFR-TKIs by attenuating the downstream FAK/SRC/AKT/MAPK signaling pathway. In H1975 cell xenograft mouse models, knockdown of ITGA8 significantly increased tumor growth and reduced the sensitivity to abivertinib, whereas overexpression of ITGA8 markedly suppressed tumor proliferation and enhanced sensitivity to the drug. This study demonstrates that ITGA8 inhibits the proliferation, invasion and migration of lung adenocarcinoma cells, enhances the sensitivity to EGFR-TKIs, improves treatment efficacy, and delays the progression of acquired resistance. Thus, ITGA8 presents a potential therapeutic candidate for addressing acquired resistance to EGFR-TKIs from a novel perspective.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982485","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":"YTHDF3-mediated FLCN/cPLA2 axis improves cardiac fibrosis via suppressing lysosomal function.","authors":"Yue Zhang, Hong-Tao Diao, Ming-Yang Leng, Ying-Zi Wu, Bing-Ying Huang, Xu Li, Wen-Yue Tang, Kai-Li Wu, Hui-Ling Tan, Liang Wang, Wen Lu, Ao Xiong, Xiao-Qi Shao, Hai-Hai Liang, Jiao Guo","doi":"10.1038/s41401-024-01425-2","DOIUrl":"https://doi.org/10.1038/s41401-024-01425-2","url":null,"abstract":"<p><p>Cardiac fibrosis characterized by aberrant activation of cardiac fibroblasts impairs cardiac contractile and diastolic functions, inducing the progression of the disease towards its terminal phase, resulting in the onset of heart failure. Therefore, the inhibition of cardiac fibrosis has become a promising treatment for cardiac diseases. The ovarian follicle-stimulating hormone folliculin (FLCN) plays a significant role in various biological processes, such as lysosome function, mitochondrial synthesis, angiogenesis, ciliogenesis and autophagy. Severe heart failure was observed in FLCN knockout mice. In this study, we investigated the role of FLCN in cardiac fibrosis and its potential mechanisms. The mice were subjected to transverse aortic constriction (TAC) surgery. Myocardial fibrosis developed in the mice 8 weeks after surgery. We showed that the protein and mRNA expression levels of FLCN were significantly decreased in TAC mice. Similar results were observed in primary mouse cardiac fibroblasts treated with Ang-II, an in vitro cardiac fibrosis model, suggesting that FLCN is involved in the pathological process of cardiac fibrosis. We demonstrated that overexpression of FLCN inhibited lysosome function in cardiac fibroblasts. Furthermore, overexpression of FLCN protected the heart from TAC-induced pathological cardiac fibrosis. We revealed that FLCN bound to the cPLA2 protein, increased its activity, regulated lysosomal function, and promoted membrane permeabilisation in cardiac fibroblasts during cardiac fibrosis. Knockdown of cPLA2 blocked the antifibrotic effect of FLCN in cardiac fibrosis. In addition, we found that the reduced expression of FLCN in cardiac fibrosis resulted from the modulation of YTHDF3-regulated m⁶A methylation of FLCN mRNA. The overexpression of YTHDF3 alleviated the production of collagens and improved cardiac structure and function in TAC mice. YTHDF3 inhibited proliferation and differentiation and regulated lysosomal function in mouse cardiac fibroblasts, whereas these effects were abolished by FLCN knockdown. We conclude that FLCN undergoes YTHDF3-regulated m⁶A modification and interacts with cPLA2 to improve lysosomal function in cardiac fibroblasts, highlighting its role in myocardial fibrosis therapy. These results suggest that FLCN and YTHDF3 could serve as potential therapeutic targets for cardiac fibroblast treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976968","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":"Endothelial Gsα deficiency promotes ferroptosis and exacerbates atherosclerosis in apolipoprotein E-deficient mice via the inhibition of NRF2 signaling.","authors":"Li-Fan He, Lei Wang, Jing-Wei Li, Xiao Xiong, Xiao-Lin Yue, Pei-Dong Yuan, Han-Lin Lu, Jian-Gang Gao, Fang-Pu Yu, Min Chen, Lee S Weinstein, Jian-Min Yang, Cheng Zhang, Xiaoteng Qin, Wencheng Zhang","doi":"10.1038/s41401-024-01446-x","DOIUrl":"https://doi.org/10.1038/s41401-024-01446-x","url":null,"abstract":"<p><p>The importance of ferroptosis in the occurrence and progression of atherosclerosis is gradually being recognized. The stimulatory G protein α subunit (Gsα) plays a crucial role in the physiology of endothelial cells (ECs). Our previous study showed that endothelial Gsα could regulate angiogenesis and preserve endothelial permeability. In this study, we investigated whether endothelial Gsα contributed to atherosclerosis through ferroptosis and oxidative stress. We generated endothelial Gsα-specific knockout mice in apolipoprotein E-deficient (ApoE^-/-) background (ApoE^-/-Gsα^ECKO), and found that the mice exhibited aggravated atherosclerotic lesions and signs of ferroptosis compared with their wild-type littermates (ApoE^-/-Gsα^fl/fl). In human aortic endothelial cells (HAECs), overexpression of Gsα reduced lipid peroxidation and ferroptosis, whereas Gsα knockdown exacerbated oxidative stress and ferroptosis. Further, Gsα overexpression in HAECs increased the expression of antioxidant genes nuclear factor erythroid 2-related 2 (NRF2) and its downstream genes. Gsα regulated the expression of NRF2 through CCCTC-binding factor (CTCF). In conclusion, this study has revealed that Gsα acts as a defense factor against endothelial ferroptosis and is a potential target for the treatment of atherosclerosis and associated ischemic heart disease. A model depicting the increase in the endothelial Gsα protein level in response to atherosclerotic stimuli. Gsα regulates NRF2 expression through cAMP/Epac/CTCF-mediated transcription and inhibits ferroptosis. Endothelial Gsα deficiency alleviates antioxidative stress and exacerbates atherosclerosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976957","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}