Pharmacological research最新文献

{"title":"Cardiac PDK4 promotes neutrophilic PFKL methylation and drives the innate immune response in diabetic myocardial infarction","authors":"Song Yang ,&nbsp;Longxin Yan ,&nbsp;Lang Chen ,&nbsp;Gaijuan Su ,&nbsp;Long Yang ,&nbsp;Lili Gong ,&nbsp;Lihong Liu","doi":"10.1016/j.phrs.2025.107731","DOIUrl":"10.1016/j.phrs.2025.107731","url":null,"abstract":"<div><div>NETosis plays a pivotal role in the innate immune response after diabetic myocardial infarction (MI), exerting a profound influence on the overall pathological process and potential recovery outcomes. The metabolism of diabetic cardiomyocyte actively creates a specialized micro environment for the innate immune response after MI. However, the mechanism by which cardiac metabolism drives NETosis remains unclear. Utilizing public databases of human MI sc-RNA datasets, we discovered that cardiomyocyte PDK4 expression mediates the intensification of glycolysis, which is strongly correlated with NETosis. Through mass spectrometry imaging and phenotype assessment, we ascertained that specific knockout of PDK4 in cardiomyocytes (PDK4^fl/flMyh6^Cre, male, 6 weeks) led to a reduction in NETosis by restraining micro environmental lactate (LA) production. In addition, the role of LA in promoting NETosis has been further corroborated by <em>in vivo</em>/<em>in vitro</em> experiments involving LA supplementation and its absence. Moreover, LA redirects neutrophil metabolic flux from glycolysis to the pentose-phosphate pathway (PPP). Mechanistically, LA triggers metabolic remodeling through the PRMT9-mediated methylation of PFKL at the R301 residue, resulting in PFKL inactivation and the consequent restriction of glycolysis. Our findings reveal the crucial role of cardiomyocyte metabolism in NETosis, shedding light on the role of LA as a vital signaling molecule in the crosstalk between cardiomyocytes and neutrophils. Importantly, we screened pitavastatin, a potential inhibitor of PDK4 among the FDA-approved drugs, and verified that it can alleviate NETosis in diabetic MI, which provides a rationale for drug selection in diabetic MI patients.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107731"},"PeriodicalIF":9.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143830189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of semaphorin 3A in the pathogenesis and progression of Alzheimer’s disease and other aging-related diseases: A comprehensive review","authors":"Jiayu Yuan ,&nbsp;Rui Huang ,&nbsp;Jianfei Nao ,&nbsp;Xiaoyu Dong","doi":"10.1016/j.phrs.2025.107732","DOIUrl":"10.1016/j.phrs.2025.107732","url":null,"abstract":"<div><div>Aging serves as a pivotal factor in the etiology of numerous diseases, such as Alzheimer's disease (AD), Parkinson's disease, diabetes, osteoarthritis, atherosclerosis and aging-related macular degeneration. Notably, these diseases often interact with AD through various pathways, facilitating the onset or progression of one another. Semaphorin 3 A (Sema3A), a protein that is essential for axonal guidance during neural development, has recently been identified as a novel regulator in the pathogenesis and progression of multiple aging-related diseases. This article provides a comprehensive review of the expression patterns and mechanisms of action of Sema3A in these diseases. Specifically, Sema3A influences the occurrence and development of aging-related diseases by participating in oxidative stress, inflammatory responses, apoptosis, and synaptic plasticity. Therefore, therapeutic strategies targeting Sema3A present promising avenues for delaying the progression of aging-related diseases and offer novel insights and strategies for their treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107732"},"PeriodicalIF":9.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826364","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":"Artificial intelligence in central-peripheral interaction organ crosstalk: the future of drug discovery and clinical trials","authors":"Yufeng Chen ,&nbsp;Mingrui Yang ,&nbsp;Qian Hua","doi":"10.1016/j.phrs.2025.107734","DOIUrl":"10.1016/j.phrs.2025.107734","url":null,"abstract":"<div><div>Drug discovery before the 20th century often focused on single genes, molecules, cells, or organs, failing to capture the complexity of biological systems. The emergence of protein-protein interaction network studies in 2001 marked a turning point and promoted a holistic approach that considers the human body as an interconnected system. This is particularly evident in the study of bidirectional interactions between the central nervous system (CNS) and peripheral organs, which are critical for understanding health and disease. Understanding these complex interactions requires integrating multi-scale, heterogeneous data from molecular to organ levels, encompassing both omics (e.g., genomics, proteomics, microbiomics) and non-omics data (e.g., imaging, clinical phenotypes). Artificial intelligence (AI), particularly multi-modal models, has demonstrated significant potential in analyzing CNS-peripheral organ interactions by processing vast, heterogeneous datasets. Specifically, AI facilitates the identification of biomarkers, prediction of therapeutic targets, and simulation of drug effects on multi-organ systems, thereby paving the way for novel therapeutic strategies. This review highlights AI's transformative role in CNS-peripheral interaction research, focusing on its applications in unraveling disease mechanisms, discovering drug targets, and optimizing clinical trials through patient stratification and adaptive trial design.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107734"},"PeriodicalIF":9.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143830188","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":"Multidisciplinary consensus on the diagnosis and management of patients with atypical Hemolytic Uremic Syndrome (complement-mediated TMA): Recommendations from Italian scientific societies, patient associations and regulators","authors":"Emma Diletta Stea ,&nbsp;Mariateresa Pugliano ,&nbsp;Roberta Gualtierotti ,&nbsp;Monica Mazzucato ,&nbsp;Luisa Santangelo ,&nbsp;Giuseppina Annicchiarico ,&nbsp;Alfredo Berardelli ,&nbsp;Stefano Bianchi ,&nbsp;Laura Bogliolo ,&nbsp;Paolo Chiandotto ,&nbsp;Giuseppe Cirino ,&nbsp;Fabio De Iaco ,&nbsp;Silvia De Rosa ,&nbsp;Francesco Dentali ,&nbsp;Paola Facchin ,&nbsp;Ennio Giulio Favalli ,&nbsp;Francesco Fiorin ,&nbsp;Antonino Giarratano ,&nbsp;Claudia Laterza ,&nbsp;Francesco Macrì ,&nbsp;Annamaria De Luca","doi":"10.1016/j.phrs.2025.107714","DOIUrl":"10.1016/j.phrs.2025.107714","url":null,"abstract":"<div><div>Atypical Hemolytic Uremic Syndrome (aHUS) is a severe, systemic, rare disease (RD) that can occur in people of all ages, and is associated with high rates of morbidity and mortality. Because the management of patients with aHUS can be difficult, more effective strategies should be implemented. Faculty members from several Italian Scientific Societies, Patient Associations and Regional Institutional Experts on RDs met to discuss aHUS management within a multidisciplinary team (MDT), using a Delphi process to develop consensus recommendations. Consensus (≥70 % agreement by faculty members) was reached on 51 statements with the aim of improving patient management and outcomes. These statements provide a unified framework for the differential diagnosis of aHUS, prompt recognition of the pathology, referral to RD reference centers, selecting between treatment relapse prevention measures options, patient management by a MDT and improving the overall awareness of aHUS. Despite the broad scope of the consensus statements, several unmet needs in the management of patients with aHUS were identified, including diagnostic suspicion, rapid genetic investigations, regular review of the centers of expertise (considering the number of treated patients), permanent clinical referral in treatment centers and widespread expertise among adult and pediatric specialists. We hope that this standardized framework will form the basis of the “digital ecosystem” concept and development of possible information technology solutions to assist the MDT involved in the management of patients with aHUS.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"216 ","pages":"Article 107714"},"PeriodicalIF":9.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931383","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":"Health benefits of medicinal plant natural products via microbiota-mediated different gut axes","authors":"Xiang Li ,&nbsp;Yufan Liu ,&nbsp;Ning Liu ,&nbsp;Hanning Wu ,&nbsp;Kexin Cong ,&nbsp;Linnan Duan ,&nbsp;Tianli Chen ,&nbsp;Jie Zhang","doi":"10.1016/j.phrs.2025.107730","DOIUrl":"10.1016/j.phrs.2025.107730","url":null,"abstract":"<div><div>This review examines the multifaceted roles of medicinal plant natural products in influencing gut microbiota and their subsequent impact on various organ systems through established gut axes, including the gut-brain, gut-liver, gut-heart, gut-lung, and gut-kidney axes. Medicinal plant natural products have exhibited diverse pharmacological activities, including modulation of microbiota composition, enhancement of metabolic processes, and alleviation of inflammation and oxidative stress. Evidence suggests that these components can ameliorate conditions such as neurological disorders, metabolic syndrome, and chronic kidney disease by restoring microbial balance and improving gut barrier integrity. Furthermore, the review highlights the potential of medicinal plant natural products to foster beneficial microbial communities and improve gut health, which may lead to reduced disease severity and inflammation. By comprehensively analyzing current literature, this review provides a foundation for future research aim at exploring the therapeutic applications of medicinal plant natural products in disease prevention and treatment. The findings underscore the need for further studies to elucidate the underlying mechanisms of action and validate the clinical efficacy of medicinal plant natural products in managing chronic conditions through gut microbiota modulation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107730"},"PeriodicalIF":9.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821240","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":"Shenxiong Yixin Decoction polysaccharides exert therapeutic effects against myocardial ischemia-reperfusion injury via intestinal exosomal microRNA-21 regulation","authors":"De-Sheng Xu ,&nbsp;Yan Wang ,&nbsp;Zi-Rui Li ,&nbsp;Ping-Li Mo ,&nbsp;Ming-Tai Chen ,&nbsp;Rui-Zhi Zhao ,&nbsp;Zheng Fan ,&nbsp;Wen-Jie Mo ,&nbsp;Qi-Lu Li ,&nbsp;Fang-Cao Pi ,&nbsp;Qi-Di Sun ,&nbsp;Juan-Min Li ,&nbsp;Yun-Da Yao ,&nbsp;Jian-Ping Chen ,&nbsp;Yuan-Yuan Li ,&nbsp;Jie-Nan Luan ,&nbsp;Shang-Bin Zhang ,&nbsp;Ying Xie ,&nbsp;Hua Zhou","doi":"10.1016/j.phrs.2025.107725","DOIUrl":"10.1016/j.phrs.2025.107725","url":null,"abstract":"<div><div><em>Background and Objective:</em> Myocardial ischemia-reperfusion injury (MIRI) presents a prevalent global clinical challenge without an optimal treatment strategy. Shenxiong Yixin Decoction exhibits promising cardioprotective effects in clinical scenarios. Polysaccharides, particularly pivotal in cardioprotection, act systemically through the intestine. Exosomes, particularly miRNA-rich ones, are crucial in MIRI pathophysiology. However, the specific role of gut-derived exosomal miRNAs in cardiovascular disease remains unclear. This study aimed to evaluate the cardioprotective effects of Shenxiong Yixin Decoction polysaccharides (SXYXP) on MIRI and elucidate its mechanisms.</div></div><div><h3>Methods</h3><div><em>In vitro and in vivo</em> models of MIRI were set up with H9c2 cells, C57BL/6 mice, and Sprague-Dawley rats. Exosomes from IEC-6 cells and plasma were detected. Various techniques like MTT, TTC, H&amp;E staining, echocardiography, flow cytometry, immunofluorescence, RT-qPCR, and Western blot were employed for pharmacodynamic and mechanistic analyses.</div></div><div><h3>Results</h3><div>SXYXP treatment could reduce myocardial infarction area, improve cardiac function, and increase myocardial cell survival rate under MIRI. The SXYXP treatment significantly enhanced the release of enterocyte-derived exosomes and elevated the levels of miR-21 within these exosomes. These SXYXP-modulated exosomes demonstrated a significant protective effect against H/R injury in H9c2 cells. However, the application of miR-21 inhibitors in the SXYXP group negated the protective effects of exosomes, leading to diminished cardiomyocyte proliferation, exacerbated oxidative stress, and elevated apoptosis.</div></div><div><h3>Conclusion</h3><div>SXYXP may protect against MIRI by targeting miR-21 in intestinal cell-derived exosomes, which are transported to the heart through the blood to restore the level of miR-21 in the damaged myocardium, thereby inhibiting oxidative stress and the expression of PDCD4.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107725"},"PeriodicalIF":9.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143824035","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":"Traditional Chinese medicine and natural products in management of hepatocellular carcinoma: Biological mechanisms and therapeutic potential","authors":"Yunqing Xun ,&nbsp;Guang Chen ,&nbsp;Guoyi Tang ,&nbsp;Cheng Zhang,&nbsp;Shichen Zhou,&nbsp;Tung-Leong Fong,&nbsp;Yue Chen,&nbsp;Ruogu Xiong,&nbsp;Ning Wang,&nbsp;Yibin Feng","doi":"10.1016/j.phrs.2025.107733","DOIUrl":"10.1016/j.phrs.2025.107733","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC), originating from hepatocytes, is the most common type of primary liver cancer. HCC imposes a significant global health burden with high morbidity and mortality, making it a critical public concern. Surgical interventions, including hepatectomy and liver transplantation, are pivotal in achieving long-term survival for patients with HCC. Additionally, ablation therapy, endovascular interventional therapy, radiotherapy, and systemic anti-tumor therapies are commonly employed. However, these treatment modalities are often associated with considerable challenges, including high postoperative recurrence rates and adverse effects. Traditional Chinese medicine (TCM) and natural products have been utilized for centuries as a complementary approach in managing HCC and its complications, demonstrating favorable clinical outcomes. Various bioactive compounds derived from TCM and natural products have been identified and purified, and their mechanisms of action have been extensively investigated. This review aims to provide a comprehensive and up-to-date evaluation of the clinical efficacy of TCM, natural products and their active constituents in the treatment and management of HCC. Particular emphasis is placed on elucidating the potential molecular mechanisms and therapeutic targets of these agents, including their roles in inhibiting HCC cell proliferation, inducing apoptosis and pyroptosis, suppressing tumor invasion and metastasis, and restraining angiogenesis within HCC tissues.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107733"},"PeriodicalIF":9.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143826365","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":"Natural compounds targeting ferroptosis in ovarian cancer: Research progress and application potential","authors":"Yuanyuan Zhao ,&nbsp;Lichao Lu ,&nbsp;Xingying Chen ,&nbsp;Qiaozhi Yin","doi":"10.1016/j.phrs.2025.107729","DOIUrl":"10.1016/j.phrs.2025.107729","url":null,"abstract":"<div><div>Ovarian cancer (OC) is among the most common malignancies in the female reproductive system, marked by high rates of recurrence and mortality. Conventional chemotherapy, however, faces limitations due to the development of drug resistance, which hinders its effectiveness. Ferroptosis, an atypical form of programmed cell death distinct from autophagy, apoptosis, and necrosis, the relationship with tumors has become a hot research area in cancer studies in recent years. Anticancer therapies that target ferroptosis show strong potential in improving prognosis and counteracting chemotherapy resistance. Natural compounds, as a valuable source of novel targeted anticancer agents, its significant role in inhibiting tumor cell proliferation and metastasis and improving therapeutic sensitivity has been demonstrated in numerous existing studies. This review summarizes a range of natural compounds that target ferroptosis in OC cells, discussing their active components, mechanisms of action, and therapeutic potential, thereby providing useful insights for future targeted therapy and research in OC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107729"},"PeriodicalIF":9.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803941","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":"Breaking the synergism of iron overload and miR-122 to rescue lipid accumulation and peroxidation in MASLD","authors":"Yuxiao Tang ,&nbsp;Zelong Gao ,&nbsp;Jianxin Yang ,&nbsp;Chenqi Li ,&nbsp;Weili Wang ,&nbsp;Chenghua Wu ,&nbsp;Mengpu Wu ,&nbsp;Min Li ,&nbsp;Huiwen Wu ,&nbsp;Yan Sun ,&nbsp;Hongwei Zhang ,&nbsp;Yifeng Chai ,&nbsp;Feng Xie ,&nbsp;Jianxin Qian ,&nbsp;Hui Shen ,&nbsp;Dongyao Wang","doi":"10.1016/j.phrs.2025.107728","DOIUrl":"10.1016/j.phrs.2025.107728","url":null,"abstract":"<div><div>MASLD is a multifactorial disease with specific subtypes being featured by hepatic iron overload and loss of miR-122, a liver-specific microRNA regulating hepatic lipid homeostasis. Previously we reported the mechanism of iron overload decreasing miR-122. Interestingly, we found that mice lacking miR-122 were highly sensitive to iron overload-induced steatosis and fibrosis. The present study aimed to disclose the downstream mechanisms and the preventive measures targeting miR-122. We first validated the decreases in iron-related genes and miR-122 in MASLD. By using LC-MS/MS and gas-chromatography, we found that the combination of miR-122 knockout and iron overload significantly increased the production and peroxidation of polyunsaturated fatty acids (PUFAs). However, miR-122 knockout itself only incurred lipid accumulation, suggesting a synergistic effect of miR-122 knockout and iron overload in lipid peroxidation. We then located the key enzymes involved in PUFA production and peroxidation by the transcriptome and proteome analysis. Mechanistically, miR-122 and iron regulated fatty acid synthesis through Aacs, fatty acid desaturation through Fads2, and PUFAs oxidation through CYPs. Re-supplementation of miR-122 by recombinant adeno-associated virus or agomir effectively broke the synergism of miR-122 knockout and iron overload in vivo. We further designed a miR-122 expression reporter cell model for high-throughput screening on 2543 natural compounds, and eventually found and validated that the dihydroberberine could upregulate miR-122 expression and correct iron overload-induced lipid disorders. These results identified the synergistic role of miR-122 and iron in PUFAs production and peroxidation, and also proposed the potential application of dihydroberberine as a preventive and therapeutic candidate for MASLD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107728"},"PeriodicalIF":9.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143792615","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":"NAALAD2 mutations disrupt the fate of photoreceptor cells and retinal pigment epithelial cells during early retinal development","authors":"Yuanjie Qian ,&nbsp;Jian Gao ,&nbsp;Zheming Zhang ,&nbsp;Yixuan Chen ,&nbsp;Jindi Su ,&nbsp;Xing Niu ,&nbsp;Kaifeng Zheng ,&nbsp;Yantao Bao ,&nbsp;Yueyuan Qin ,&nbsp;Junge Zheng ,&nbsp;Yuankai Yang ,&nbsp;Qunyan Wu ,&nbsp;Ke Mo ,&nbsp;Yantao Wei ,&nbsp;Shan Duan","doi":"10.1016/j.phrs.2025.107724","DOIUrl":"10.1016/j.phrs.2025.107724","url":null,"abstract":"<div><div>In recent years, the global incidence of myopia has steadily increased, highlighting the importance of prevention and early intervention, particularly in the absence of effective treatments. Here, we identified a previously unreported mutation in the human N-acetylated alpha-linked acidic dipeptidase 2 (NAALAD2) gene (c.2109 T &gt; G, p.F703L) considered in a Chinese family with pathological myopia (PM). We explored the potential link between NAALAD2 mutation and the development of PM by using the Naalad2 point mutation knock-in mouse models. Through single-cell RNA sequencing, we analyzed the retinal cell composition and transcriptional profiles both in Naalad2^+/+ and Naalad2^+/- mice, especially the changes in Cone photoreceptor cells, Rod photoreceptor cells and retinal pigment epithelial (RPE) cells. We found that the Naalad2 mutation led to a reduction in the abundance of Cone and Rod photoreceptor cells, along with upregulation of immediate early genes and abnormal differentiation of certain cell subpopulations. Additionally, RPE cell subpopulations exhibited a fibrotic tendency, disrupting their interactions with photoreceptor cells. Moreover, this study suggests that NAALAD2 mutation may accelerate retinal degeneration by influencing photoreceptor cell apoptosis, stress responses, and the epithelial-mesenchymal transition process in RPE cells. These findings provide new insights into the pathogenic mechanisms of NAALAD2 mutations in PM and offer potential therapeutic targets for future PM research.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"215 ","pages":"Article 107724"},"PeriodicalIF":9.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788746","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}