Molecular Medicine最新文献

{"title":"Endogenous Galectin-8 protects against Th17 infiltration and fibrosis following acute kidney injury.","authors":"Elisa Perez-Moreno, Adely de la Peña, Tomás Toledo, Javiera Saez, Francisca Pérez-Molina, Sofía Espinoza, Claudia Metz, Nicole Díaz-Valdivia, Lorena Azócar, Carolina Prado, Rodrigo Pacheco, Fabian Segovia-Miranda, Alejandro S Godoy, Cristian A Amador, Teo Feuerhake, Alfonso González, Andrea Soza","doi":"10.1186/s10020-025-01245-y","DOIUrl":"10.1186/s10020-025-01245-y","url":null,"abstract":"<p><strong>Background: </strong>Acute kidney injury (AKI) is a serious clinical condition characterized by a rapid decline in renal function, often progressing to chronic kidney disease (CKD) and fibrosis. The endogenous mechanisms influencing kidney injury resolution or maladaptive repair remain poorly understood. Galectin-8 (Gal-8), a tandem-repeat β-galactoside-binding lectin, plays a role in epithelial cell proliferation, epithelial-mesenchymal transition, and immune regulation, all of which are critical in AKI outcomes. While exogenous Gal-8 administration has shown renoprotective effects, its endogenous role in kidney injury progression and resolution remains unclear.</p><p><strong>Methods: </strong>To investigate the endogenous role of Gal-8 in AKI, we compared the responses of Gal-8 knockout (Gal-8-KO; Lgals8^-/- bearing a β-gal cassette under the Lgals8 gene promoter) and wild-type (Lgals8^+/+) mice in a nephrotoxic folic acid (FA)-induced AKI model. Renal Gal-8 expression was assessed by β-galactosidase staining, lectin-marker colocalization, and RT-qPCR. Renal function, structure, and immune responses were evaluated at the acute (day 2) and fibrotic (day 14) phases of injury. Plasma creatinine levels were measured to assess renal function, while histological analyses evaluated tubular damage, renal inflammation, and extracellular matrix deposition. Flow cytometry was performed to characterize the immune response, focusing on pro-inflammatory T cells.</p><p><strong>Results: </strong>Galectin-8 was predominantly expressed in the renal cortex, localizing to tubules, glomeruli, and blood vessels, with its levels decreasing by half following AKI. Both Lgals8^+/+ and Lgals8^-/- mice exhibited similar renal function and structure impairments during the acute phase, though Lgals8^+/+ mice showed slightly worse damage. By the fibrotic phase, Lgals8^-/- mice exhibited more pronounced cortical damage and fibrosis, characterized by increased type I and III collagen deposition and enhanced Th17 cell infiltration, while myofibroblast activation remained comparable to that of Lgals8^+/+ mice.</p><p><strong>Conclusions: </strong>Endogenous Gal-8 does not significantly protect the kidney during the acute phase and is dispensable for cell proliferation and death in response to AKI. However, it is crucial in preventing maladaptive repair by regulating extracellular matrix homeostasis and mitigating fibrosis. Additionally, Gal-8 contributes to inflammation resolution by limiting persistent immune cell infiltration, particularly IL-17-secreting cells.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"192"},"PeriodicalIF":6.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Science tikkun: a bioscience pandemic framework in a Hebrew tradition of global repair.","authors":"Peter Hotez","doi":"10.1186/s10020-025-01244-z","DOIUrl":"https://doi.org/10.1186/s10020-025-01244-z","url":null,"abstract":"<p><p>Over the past decade we have seen a steady increase in dangerous pandemic threats. They include two major Ebola epidemics and cholera in Africa; dengue, Zika, yellow fever in the Americas; a COVID-19 pandemic; and H5N1 in Texas. This is happening because of a confluence of modern forces including urbanization, deforestation, and climate change. Yet as pandemics emerge on a crowded and warming planet, anti-science disinformation and antisemitism impede our response. Science tikkun is an overarching framework for repair and redress. It honors the legacy of Maimonides, Teilhard de Chardin, and others who have sought reconciliation between science and religion.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"193"},"PeriodicalIF":6.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086401","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":"Inhibition of diacylglycerol O-acyltransferase 1 provides neuroprotection by inhibiting ferroptosis in ischemic stroke.","authors":"Youjie Zeng, Ren Guo, Songhua Chen, Yuxin Lin, Si Cao, Xia Wang, Siyi Zhang, Huilin Xu, Wenxiang Qing, Heng Yang, Wen Ouyang","doi":"10.1186/s10020-025-01255-w","DOIUrl":"10.1186/s10020-025-01255-w","url":null,"abstract":"<p><strong>Background: </strong>Diacylglycerol O-acyltransferase 1 (DGAT1) is crucial for triglyceride synthesis, yet its role in ischemic stroke remains unclear. This study investigated DGAT1 in ischemic stroke using middle cerebral artery occlusion (MCAO) rat models and highly differentiated PC12 cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R).</p><p><strong>Methods: </strong>The therapeutic effects of DGAT1 inhibition in MCAO rats were assessed using the Zea-Longa score and 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The effects on highly differentiated PC12 cells subjected to OGD/R were evaluated using the Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Ferroptosis-related mitochondrial damage was evaluated using transmission electron microscope. Additionally, the mechanisms by which DGAT1 inhibition regulates ferroptosis were further explored via immunohistochemistry, immunofluorescence, Western blotting, qPCR, JC-1 assay, and reactive oxygen species (ROS) detection.</p><p><strong>Results: </strong>DGAT1 expression was elevated in both MCAO and OGD/R models. The DGAT1 inhibitor A 922500 improved neurological deficits, reduced infarct volume, and minimized neuronal loss in MCAO rats, while also enhancing cell viability and reducing LDH levels in OGD/R-treated PC12 cells. DGAT1 inhibition significantly alleviated ferroptosis in MCAO rats, as indicated by (i) reduced mitochondrial shortening and cristae disruption, (ii) decreased 4-HNE levels, (iii) reduced MDA and increased SOD, and (iv) lowered levels of inflammatory factors (IL-6, MCP-1, and TNF-α). Moreover, both in vivo and in vitro experiments showed that DGAT1 inhibition significantly increased Gpx4 levels, whereas lentiviral delivery of Gpx4 shRNA markedly reversed its beneficial effects. In MCAO rats, Gpx4 shRNA significantly elevated 4-HNE levels and exacerbated ferroptosis-related mitochondrial damage. In vitro, DGAT1 inhibition increased mitochondrial membrane potential and reduced ROS, whereas rotenone, a mitochondrial function inhibitor, decreased Gpx4 and impaired cell viability. Furthermore, DGAT1 inhibition significantly upregulated the key β-oxidation gene Cpt1a, whereas etomoxir, a β-oxidation inhibitor, reduced cell viability and mitochondrial membrane potential, increased ROS, and downregulated Gpx4.</p><p><strong>Conclusions: </strong>Our study suggests that DGAT1 inhibition may enhance β-oxidation and mitochondrial function, thereby increasing Gpx4 levels, suppressing ferroptosis, and ultimately exerting neuroprotective effects in ischemic stroke.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"191"},"PeriodicalIF":6.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipocalin-2-mediated ferroptosis as a target for protection against light-induced photoreceptor degeneration.","authors":"Wenyi Tang, Ruyi Zhai, Jun Ma, Gezhi Xu","doi":"10.1186/s10020-025-01250-1","DOIUrl":"10.1186/s10020-025-01250-1","url":null,"abstract":"<p><strong>Background: </strong>Retinal degeneration is a leading cause of blindness worldwide. The induction of ferroptosis has been identified as an important mechanism contributing to the loss of photoreceptors in retinal degeneration. Lipocalin-2 (LCN2) exhibits iron-regulatory properties and may modulate cell viability in various diseases. However, the effects of LCN2 on ferroptosis in retinal degeneration remain unclear.</p><p><strong>Methods: </strong>A light-induced injury model using 661W photoreceptor cells and a light-induced retinal degeneration male rat model were established. LCN2 protein expression was assessed by western blotting. The effects of LCN2 on ferroptosis in vitro were investigated by using recombinant LCN2 protein (rLCN2) and small-interfering RNA (siRNA) targeting LCN2 (siLCN2). Fe²⁺, malondialdehyde (MDA), tripeptide glutathione (GSH) levels, and the expression of ferroptosis-associated proteins (solute carrier family 7 member 11 [SLC7A11] and glutathione peroxidase-4 [GPX4]) were measured. A phosphokinase array and western blotting were performed to elucidate the mechanisms underlying LCN2-modulated photoreceptor ferroptosis. Additionally, the protective effects of LCN2 knockdown using adeno-associated virus (AAV)-expressing short hairpin RNA (shRNA) targeting LCN2 (AAV-shRNA-LCN2) on retinal structure and function in vivo were evaluated by hematoxylin and eosin staining and electroretinography.</p><p><strong>Results: </strong>LCN2 expression was significantly upregulated following light exposure. Treatment with rLCN2 significantly induced ferroptosis in photoreceptor cells, as shown by decreased cell viability, increased Fe²⁺ levels, inhibition of SLC7A11 and GPX4 expression, depletion of GSH, and enhanced MDA levels, whereas siLCN2 protected against these effects. Exposure of photoreceptor cells to rLCN2 activated c-Jun N-terminal kinase (JNK), and administration of the JNK inhibitor SP600125 protected photoreceptor cells from ferroptosis. Lastly, AAV-shRNA-LCN2 administration inhibited light-induced ferroptosis in the retina, and protected the retinal structure and function in vivo.</p><p><strong>Conclusion: </strong>LCN2 is a key regulator of light-induced ferroptosis in photoreceptors by modulating the JNK pathway. Therefore, LCN2 presents a new target for the treatment of retinal degeneration.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"190"},"PeriodicalIF":6.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AEOL-induced NRF2 activation and DWORF overexpression mitigate myocardial I/R injury.","authors":"Maria Del Carmen Asensio-Lopez, Miriam Ruiz-Ballester, Silvia Pascual-Oliver, Francisco Jose Bastida-Nicolas, Yassine Sassi, Jose Javier Fuster, Domingo Pascual-Figal, Fernando Soler, Antonio Lax","doi":"10.1186/s10020-025-01242-1","DOIUrl":"10.1186/s10020-025-01242-1","url":null,"abstract":"<p><strong>Background: </strong>The causal relationship between the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the preservation of SERCA2a function in mitigating myocardial ischemia-reperfusion (mI/R) injury, along with the associated regulatory mechanisms, remains incompletely understood. This study aims to unravel how NRF2 directly or indirectly influences SERCA2a function and its regulators, phospholamban (PLN) and Dwarf Open Reading Frame (DWORF), by testing the pharmacological repositioning of AEOL-10150 (AEOL) in the context of mI/R injury.</p><p><strong>Methods: </strong>C57BL6/J, Nrf2 knockout (Nrf2^-/-), and wild-type (Nrf2^+/+) mice, as well as human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) were subjected to I/R injury. Gain/loss of function techniques, RT-qPCR, western blotting, LC/MS/MS, and fluorescence spectroscopy were utilized. Cardiac dimensions and function were assessed by echocardiography.</p><p><strong>Results: </strong>In the early stages of mI/R injury, AEOL administration reduced mitochondrial ROS production, decreased myocardial infarct size, and improved cardiac function. These effects were due to NRF2 activation, leading to the overexpression of the micro-peptide DWORF, consequently enhancing SERCA2a activity. The cardioprotective effect induced by AEOL was diminished in Nrf2^-/- mice and in Nrf2/Dworf knockdown models in hiPSCMs subjected to simulated I/R injury. Our data show that AEOL-induced NRF2-mediated upregulation of DWORF disrupts the phospholamban-SERCA2a interaction, leading to enhanced SERCA2a activation and improved cardiac function.</p><p><strong>Conclusions: </strong>Taken together, our study reveals that AEOL-induced NRF2-mediated overexpression of DWORF enhances myocardial function through the activation of the SERCA2a offering promising therapeutic avenues for mI/R injury.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"189"},"PeriodicalIF":6.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive single-cell transcriptomic reveals different destinies of melanocytes and dynamic changes of immune microenvironment in a psychological stress-induced leukoderma and leukotrichia mouse model.","authors":"Xuechen Cao, Yongkai Yu, Hang Yao, Yujie Zheng, Jiawei Lu, Yifei Feng, Tongxin Pei, Ziyu Li, Ming Lu, Yan Lu","doi":"10.1186/s10020-025-01236-z","DOIUrl":"10.1186/s10020-025-01236-z","url":null,"abstract":"<p><strong>Background: </strong>Vitiligo is an acquired skin depigmentation disorder often accompanied by leukoderma and leukotrichia. Half of vitiligo patients experience episodes of stress.</p><p><strong>Methods: </strong>We established a chronic unpredictable mild stimulation (CUMS) model in C57BL/6 J mice to simulate chronic mental stress-induced leukoderma and leukotrichia. Single-cell RNA sequencing was performed to determine the immune landscape and to characterize the relationship between immune-stromal cells. Immunohistochemistry was employed for validation.</p><p><strong>Results: </strong>We discovered a similar pro-inflammatory micro-environment composed of keratinocytes and fibroblasts similar to that in human vitiligo. Macrophages in CUMS mice expressed high levels of inflammatory factors and were inclined to an M1 pro-inflammatory phenotype. Two distinct clusters of melanocytes were also identified: Mel2, defined as melanocyte stem cells, and Mel3, defined as mature melanocytes. Mel2 cells were prone to pyroptosis and necroptosis, while Mel3 cells were susceptible to oxidative stress, mitochondrial dysfunction, and ferroptosis. Compared with control mice, higher expression of CXCL16 on dendritic cells and of the CXCL16 ligand, CXCR6, on γδT cells were observed in leukoderma. Dendritic cells and natural killer T cells in the CUMS mouse spleen exhibited elevated levels of CXCL16 and CXCR6, respectively. Activation of the CXCL16-CXCR6 axis and a non-specific immune response in our CUMS model might imitate chronic mental stress-induced vitiligo in humans better than CD8 + cytotoxic T lymphocyte-mediated models.</p><p><strong>Conclusions: </strong>We discovered two melanocyte clusters with distinct fates and a pro-inflammatory micro-environment with CXCL16-CXCR6 axis activation of antigen-presenting cells and other innate immunocytes that might provide new insights into the pathogenesis of stress-induced vitiligo.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"186"},"PeriodicalIF":6.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting GPR84 to alleviate acute immune-mediated liver injury.","authors":"Yanan Zheng, Yumeng Wang, Yujie Xu, Shanshan Shen, Haozhe Xu, Chao Hu, Yongzhen Chen, Fengmeng Teng, Jinshun Pan, Shuqian Zheng, Junqi Wang, Zhongping Su, Qiang You","doi":"10.1186/s10020-025-01248-9","DOIUrl":"https://doi.org/10.1186/s10020-025-01248-9","url":null,"abstract":"<p><strong>Background: </strong>GPR84 is a Gi-coupled G-protein-coupled receptor (GPCR) predominantly expressed in immune cells, with its expression upregulated during inflammatory conditions. However, its specific role in immune-mediated liver injury remains unclear.</p><p><strong>Methods: </strong>We utilized a concanavalin A (Con A)-induced mouse model to simulate immune-mediated liver injury. The expression of GPR84 was assessed by quantitative RT-PCR and western blotting. GPR84 gene knockout mice were employed to evaluate the receptor's functional role. Bone marrow chimeric mice were created to determine the involvement of hematopoietic cells. Infiltrating liver inflammatory cells were analyzed by flow cytometry. The activation of key signaling pathways in hepatic tissues was assessed by western blotting. The GPR84 antagonist GLPG1205 was tested in this model to evaluate its therapeutic potential.</p><p><strong>Results: </strong>GPR84 expression was significantly upregulated in the mouse liver following Con A injection. Mice lacking GPR84 exhibited reduced serum ALT and AST levels, diminished liver damage, and decreased apoptosis. Additionally, the expression levels of inflammatory cytokines MCP-1 and TNF-α were significantly lower in Gpr84^-/- mice compared to wild-type (WT) mice after Con A injection. Flow cytometry analysis revealed a notable reduction in the proportion of Kupffer cells and infiltrating monocytes (CD11b⁺Ly6C^lowLy6G⁻) in Gpr84^-/- mice. Using bone marrow chimeric mice, we demonstrated that GPR84-deficient bone marrow-derived cells mitigate Con A-induced liver injury. Furthermore, GPR84 deficiency was associated with reduced hepatic apoptosis and lower phosphorylation levels of STAT3, ERK, JNK, p38, and p65, effectively inhibiting key inflammatory signaling pathways. Importantly, treatment with the GPR84 antagonist GLPG1205 significantly lowered serum ALT and AST levels, reduced the expression of inflammatory cytokines, and alleviated liver damage.</p><p><strong>Conclusions: </strong>Our findings suggest that GPR84 plays a pivotal role in immune-mediated liver injury, primarily through its expression on hematopoietic cells. Targeting GPR84, particularly with the antagonist GLPG1205, offers a promising therapeutic strategy for treating immune-related liver diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"187"},"PeriodicalIF":6.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12080032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arctiin, a lignan compound, enhances adipose tissue browning and energy expenditure by activating the adenosine A_2A receptor.","authors":"Yuanfeng Gu, Wenjun He, Wenxuan Li, Jingshu Cai, Zhuyun Wang, Kemeng Li, Guangcheng Qin, Xiaojie Gu, Xiaojing Lin, Li Ma, Xiaoqiu Xiao, Yi Hou, Ting Luo","doi":"10.1186/s10020-025-01249-8","DOIUrl":"https://doi.org/10.1186/s10020-025-01249-8","url":null,"abstract":"<p><strong>Background: </strong>The activation of brown adipose tissue (BAT) or the browning of white adipose tissue (WAT) represents a promising therapeutic strategy for obesity. Arctiin (ARC), a lignan compound known for its anti-inflammatory, anti-tumor, and hypoglycemic properties, has not been fully elucidated regarding its effects and mechanisms on obesity.</p><p><strong>Methods: </strong>In the present study, we established both high-fat diet-induced obese mouse models and mature adipocyte cultures to comprehensively investigate the therapeutic effects of ARC on obesity. Systemic energy metabolism and thermogenic capacity were assessed through metabolic cage monitoring and cold stimulation tests. Histopathological alterations in adipose tissues were examined using hematoxylin and eosin (H&E) staining, while key gene expression in adipocytes was determined by Western blotting (WB), immunohistochemistry, and immunofluorescence staining. To further elucidate the molecular mechanisms underlying ARC's anti-obesity effects, we employed an integrated approach combining network pharmacology analysis, molecular docking simulations, cellular thermal shift assay (CETSA), and WB to identify potential molecular targets and delineate the associated signaling pathways modulated by ARC treatment.</p><p><strong>Results: </strong>In diet-induced obese mice, ARC administration at doses of 20 and 60 mg/kg/day ameliorated metabolic dysfunction through enhanced WAT browning and increased energy expenditure. In C3H10T1/2-induced adipocytes, ARC upregulated the protein expression of uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and other brown-specific marker genes, promoting mitochondrial function and browning of adipocytes. Mechanistically, our findings suggest that ARC may promote adipocyte browning via the A_2AR-cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway.</p><p><strong>Conclusion: </strong>In summary, ARC exerts protective effects against obesity by promoting the browning of white adipocytes and holds promise as a potentially beneficial therapeutic agent for the treatment of obesity.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"188"},"PeriodicalIF":6.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK2/STAT3/HMGCS2 signaling aggravates mitochondrial dysfunction and oxidative stress in hyperuricemia-induced cardiac dysfunction.","authors":"Dewei Peng, Xiaoli He, Bowen Ren, Qian Wang, Lulu Peng, Yue Jiang, Shengqi Huo, Lintong Men, Wei Shi, Pengcheng Luo, Mengyin Zhu, Cuntai Zhang, Jiagao Lv, Li Lin, Sheng Li","doi":"10.1186/s10020-025-01246-x","DOIUrl":"10.1186/s10020-025-01246-x","url":null,"abstract":"<p><strong>Background: </strong>High uric acid levels play a critical role in cardiovascular disease pathophysiology, being closely linked to their occurrence, progression, and prognosis. To enhance prevention and treatment of hyperuricemia-related cardiovascular diseases, understanding underlying mechanisms and identifying novel therapeutic targets are essential.</p><p><strong>Methods: </strong>A hyperuricemic mouse model was established, and transcriptomic analysis of myocardial tissue was conducted using RNA sequencing. The role of HMGCS2 in hyperuricemia-induced cardiomyocytes was investigated through HMGCS2 knockout. The transcriptional regulation of HMGCS2 by STAT3 was explored via STAT3 knockdown, overexpression, and dual-luciferase reporter assays. To further elucidate the role of the JAK2/STAT3/hmgcs2 signaling pathway in hyperuricemia-induced cardiomyocytes, we overexpressed HMGCS2 while intervening in the JAK2/STAT3 pathway in vitro. The therapeutic potential of targeting the JAK2/STAT3/HMGCS2 pathway was evaluated in hyperuricemic mice using STAT3 and JAK inhibitors to assess effects on cardiac dysfunction.</p><p><strong>Results: </strong>RNA sequencing showed significant upregulation of HMGCS2 mRNA in hyperuricemic mouse cardiac tissue. Increased HMGCS2 protein levels were observed in cardiac tissue and AC16 cardiomyocytes. HMGCS2 knockdown alleviated uric acid-induced mitochondrial dysfunction, oxidative stress, and abnormal energy metabolism in AC16 cardiomyocytes. And high uric acid levels activate the IL-6/JAK2/STAT3 signaling pathway in AC16 cardiomyocytes, which regulates HMGCS2 expression. By modulating JAK2 and STAT3 expression and subsequently overexpressing HMGCS2, we identified the involvement of the JAK2/STAT3/HMGCS2 pathway in uric acid-induced mitochondrial dysfunction, oxidative stress, and energy metabolism abnormalities in AC16 cardiomyocytes. In vitro experiments demonstrated that intervention with the ruxolitinib and S3I-201 could ameliorate mitochondrial dysfunction, oxidative stress, and ATP levels in the heart tissue of hyperuricemic mice. Moreover, these treatments also reversed cardiac function abnormalities.</p><p><strong>Conclusions: </strong>The JAK2/STAT3/HMGCS2 pathway may contributes to uric acid-induced cardiac dysfunction by affecting mitochondrial function, oxidative stress, and ATP metabolism, offering a potential therapeutic strategy for mitigating high uric acid-induced cardiac damage.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"184"},"PeriodicalIF":6.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QRICH1 regulates ATF6 transcription to affect pathological cardiac hypertrophy progression.","authors":"Lihui Zhang, Hongping Chen, Guangmei Zou, Wenjuan Jia, Haibin Dong, Chunxiao Wang, Hua Wang, Yugang Liu, Da Teng, Bowen Xu, Lin Zhong, Lei Gong, Jun Yang","doi":"10.1186/s10020-025-01241-2","DOIUrl":"10.1186/s10020-025-01241-2","url":null,"abstract":"<p><strong>Background: </strong>Many studies have shown that pathological cardiac hypertrophy is associated with active endoplasmic reticulum (ER) stress. Glutamine-rich protein 1 (QRICH1), as a transcriptional regulator, belongs to the caspase recruitment domain (CARD)-containing gene family. QRICH1 has been shown to influence the outcomes of endoplasmic reticulum stress by regulating the transcription of proteostasis-related genes. In this study, we explored the role of QRICH1 in pathological cardiac hypertrophy.</p><p><strong>Methods: </strong>We observed an increased expression of QRICH1 in the hearts of humans and mice with left ventricular hypertrophy (LVH). To assess the functional impact in this context, we employed gain- and loss-of-function approaches, using AAV9 injections to establish cardiac-specific QRICH1 knockdown or overexpression models in transverse aortic constriction (TAC) or isoproterenol (ISO)-induced cardiac hypertrophy.</p><p><strong>Results: </strong>Our data indicated that cardiomyocyte-specific knockdown of QRICH1 alleviated the hypertrophic phenotype in response to TAC or ISO injection. However, overexpression of QRICH1 exacerbated cardiac hypertrophy, remodeling, dysfunction, cell apoptosis, and inflammatory responses. Mechanistically, we demonstrated that ATF6 was significantly enriched by QRICH1 in cardiomyocytes treated with ISO using RNA-seq combined with CUT&TAG analysis. ChIP-qPCR and luciferase assays further confirmed that ATF6 is a target gene of QRICH1 in cardiomyocytes under growth stimulation. Knockdown of QRICH1 in cardiomyocytes blocked ISO-mediated induction of ATF6, activation of mTORC1, and cellular growth. And all of the above was restored by the overexpression of ATF6.</p><p><strong>Conclusions: </strong>QRICH1 plays a pivotal role in cardiac hypertrophy by regulating ATF6, and QRICH1 may be a potential new therapeutic target for pathological cardiac hypertrophy.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"183"},"PeriodicalIF":6.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}