Life sciences最新文献_第6页

ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications ERCC6L通过plk1介导的有氧糖酵解促进皮肤黑色素瘤进展：机制和治疗意义。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-19 DOI: 10.1016/j.lfs.2026.124216

Mengdi Zhang , Shengbo Zhou , Bing Han , Yining Ge

Aims

To elucidate the oncogenic role and mechanistic basis of ERCC6L in cutaneous melanoma, focusing on its impact on tumor metabolism and progression.

Materials and methods

Multi-omics bioinformatics analysis of public datasets (GEO, TCGA) defined the clinical relevance of ERCC6L. In vitro functional assays (CCK-8, colony formation, Transwell, flow cytometry) were performed in melanoma cell lines following genetic manipulation. Mechanistic studies employed gene set enrichment analysis, chromatin immunoprecipitation-quantitative PCR, dual-luciferase reporter assays, western blotting, and metabolic flux analysis. The functional significance of the ERCC6L-PLK1 axis was validated in an NSG mouse subcutaneous xenograft model.

Key findings

ERCC6L is significantly upregulated in melanoma tissues, and its high expression is an independent prognostic factor for poor survival. Genetic ablation of ERCC6L potently inhibited melanoma cell proliferation, migration, invasion, and tumor growth, while promoting apoptosis. Mechanistically, ERCC6L transcriptionally activates PLK1 by directly binding to its promoter. This ERCC6L-PLK1 axis drives aerobic glycolysis (the Warburg effect), upregulating key glycolytic enzymes (GLUT1, LDHA, PKM2, HK2) and enhancing lactate production and ATP generation. Crucially, PLK1 inhibition or glycolysis blockade effectively reversed the tumor-promoting phenotypes induced by ERCC6L.

Significance

Our study identifies ERCC6L as a novel upstream transcriptional regulator of PLK1 that fuels melanoma progression by reprogramming glucose metabolism. The ERCC6L-PLK1-glycolysis axis represents a promising prognostic biomarker and a potential therapeutic target for cutaneous melanoma.

目的：阐明ERCC6L在皮肤黑色素瘤中的致瘤作用及其机制基础，重点研究其对肿瘤代谢和进展的影响。材料和方法：公共数据集（GEO， TCGA）的多组学生物信息学分析定义了ERCC6L的临床相关性。在基因操作后对黑色素瘤细胞系进行体外功能测定（CCK-8，菌落形成，Transwell，流式细胞术）。机制研究采用基因集富集分析、染色质免疫沉淀-定量PCR、双荧光素酶报告基因检测、western blotting和代谢通量分析。ERCC6L-PLK1轴的功能意义在NSG小鼠皮下异种移植模型中得到验证。关键发现：ERCC6L在黑色素瘤组织中显著上调，其高表达是生存率差的独立预后因素。基因消融ERCC6L可有效抑制黑色素瘤细胞增殖、迁移、侵袭和肿瘤生长，同时促进细胞凋亡。从机制上讲，ERCC6L通过直接结合其启动子来激活PLK1。ERCC6L-PLK1轴驱动有氧糖酵解（Warburg效应），上调关键的糖酵解酶（GLUT1、LDHA、PKM2、HK2），并促进乳酸生成和ATP生成。至关重要的是，PLK1抑制或糖酵解阻断有效地逆转了ERCC6L诱导的促肿瘤表型。意义：我们的研究发现ERCC6L是PLK1的一种新的上游转录调节因子，通过重编程葡萄糖代谢来促进黑色素瘤的进展。ercc6l - plk1 -糖酵解轴是一种有前景的预后生物标志物，也是皮肤黑色素瘤的潜在治疗靶点。

{"title":"ERCC6L promotes cutaneous melanoma progression via PLK1-mediated aerobic glycolysis: Mechanisms and therapeutic implications","authors":"Mengdi Zhang , Shengbo Zhou , Bing Han , Yining Ge","doi":"10.1016/j.lfs.2026.124216","DOIUrl":"10.1016/j.lfs.2026.124216","url":null,"abstract":"<div><h3>Aims</h3><div>To elucidate the oncogenic role and mechanistic basis of ERCC6L in cutaneous melanoma, focusing on its impact on tumor metabolism and progression.</div></div><div><h3>Materials and methods</h3><div>Multi-omics bioinformatics analysis of public datasets (GEO, TCGA) defined the clinical relevance of ERCC6L. <em>In vitro</em> functional assays (CCK-8, colony formation, Transwell, flow cytometry) were performed in melanoma cell lines following genetic manipulation. Mechanistic studies employed gene set enrichment analysis, chromatin immunoprecipitation-quantitative PCR, dual-luciferase reporter assays, western blotting, and metabolic flux analysis. The functional significance of the ERCC6L-PLK1 axis was validated in an NSG mouse subcutaneous xenograft model.</div></div><div><h3>Key findings</h3><div>ERCC6L is significantly upregulated in melanoma tissues, and its high expression is an independent prognostic factor for poor survival. Genetic ablation of ERCC6L potently inhibited melanoma cell proliferation, migration, invasion, and tumor growth, while promoting apoptosis. Mechanistically, <em>ERCC6L</em> transcriptionally activates <em>PLK1</em> by directly binding to its promoter. This ERCC6L-PLK1 axis drives aerobic glycolysis (the Warburg effect), upregulating key glycolytic enzymes (GLUT1, LDHA, PKM2, HK2) and enhancing lactate production and ATP generation. Crucially, PLK1 inhibition or glycolysis blockade effectively reversed the tumor-promoting phenotypes induced by ERCC6L.</div></div><div><h3>Significance</h3><div>Our study identifies <em>ERCC6L</em> as a novel upstream transcriptional regulator of <em>PLK1</em> that fuels melanoma progression by reprogramming glucose metabolism. The ERCC6L-PLK1-glycolysis axis represents a promising prognostic biomarker and a potential therapeutic target for cutaneous melanoma.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"389 ","pages":"Article 124216"},"PeriodicalIF":5.1,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018876","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}

引用次数: 0

Corrigendum to “Empagliflozin enhances neuroplasticity in rotenone-induced parkinsonism: Role of BDNF, CREB and Npas4” [Life Sci. 312 (1 January 2023) 121258] “恩格列净增强鱼tenone诱导的帕金森病的神经可塑性：BDNF， CREB和Npas4的作用”[生命科学]. 312 (1 January 2023) 121258。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-19 DOI: 10.1016/j.lfs.2026.124213

Hager H. Mousa, Maha H. Sharawy, Manar A. Nader

引用次数: 0

Hyperglycemia disrupts alveolar bone homeostasis by inducing stem cell senescence through Mettl3/Foxo3/Sirt1 axis in diabetic periodontitis 糖尿病牙周炎患者高血糖通过Mettl3/Foxo3/Sirt1轴诱导干细胞衰老，从而破坏牙槽骨稳态。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-18 DOI: 10.1016/j.lfs.2026.124215

Jie Zhou , Xinyue Li , Lanxi Xiao , Yanlin Zhu , Yuhan Yang , Xiang Gao

Aims

Diabetes exacerbates periodontitis by intensifying inflammatory responses and impairing tissue regeneration. Hyperglycemia-induced dysfunction of jawbone-derived bone marrow mesenchymal stem cells (BMSCs) contributes to the imbalance of bone remodeling and periodontal homeostasis. This study aimed to reveal the role and regulatory mechanism of stem cell senescence in diabetic periodontitis.

Materials and methods

Diabetic periodontitis model was established in mice by high-fat diet, streptozotocin injections and ligation. Following treatment with high glucose (HG) and Porphyromonas gingivalis lipopolysaccharide (Pg-LPS), BMSCs were analyzed for cellular senescence and m⁶A levels. Functional roles of Mettl3, Foxo3, and Sirt1 were explored by knockdown, overexpression, and pharmacological activation. MeRIP, ChIP, and RNA stability assays were employed to explore m⁶A-dependent Foxo3 degradation and its interaction with Sirt1. Therapeutic potential of Sirt1 activation was validated in vivo.

Key findings

Diabetic mice developed alveolar bone degeneration and cellular senescence pathway enrichment. HG + LPS co-stimulation induced BMSCs senescence, elevated m⁶A levels and Mettl3 expression. Mettl3 knockdown reduced senescence-associated secretory phenotypes. Mechanistically, m⁶A hypermodification on the Foxo3 coding sequence accelerated mRNA decay and impeded nuclear translocation via Ythdf2 recognition. Through its transcriptional regulation of Sirt1, Foxo3 mitigated senescence when overexpressed and exacerbated oxidative damage when knocked down. Sirt1 activation alleviated senescence in vitro and in vivo, reciprocally stabilizing Foxo3 and maintaining its transcriptional activity via deacetylation.

Significance

Hyperglycemia disrupts alveolar bone homeostasis by driving stem cell senescence through the Mettl3/Foxo3/Sirt1 axis, suggesting a promising therapeutic strategy for regenerative therapy under diabetic conditions.

目的：糖尿病通过增强炎症反应和损害组织再生来加剧牙周炎。高血糖诱导的颌骨源性骨髓间充质干细胞（BMSCs）功能障碍导致骨重塑和牙周稳态失衡。本研究旨在揭示干细胞衰老在糖尿病牙周炎中的作用及调控机制。材料与方法：采用高脂饮食、链脲佐菌素注射和结扎法建立小鼠糖尿病牙周炎模型。在高糖（HG）和牙龈卟啉单胞菌脂多糖（Pg-LPS）治疗后，分析骨髓间充质干细胞的细胞衰老和m6A水平。通过敲低、过表达和药理激活来探索Mettl3、Foxo3和Sirt1的功能作用。采用MeRIP、ChIP和RNA稳定性分析来探索m6a依赖性Foxo3降解及其与Sirt1的相互作用。Sirt1激活的治疗潜力在体内得到了验证。主要发现：糖尿病小鼠出现牙槽骨变性和细胞衰老途径富集。HG + LPS共刺激诱导骨髓间充质干细胞衰老，升高m6A水平和Mettl3表达。Mettl3敲低可减少衰老相关的分泌表型。从机制上讲，Foxo3编码序列上的m6A超修饰加速了mRNA的衰变，并通过Ythdf2识别阻碍了核易位。Foxo3通过对Sirt1的转录调控，在过表达时减轻衰老，而在被敲低时加重氧化损伤。Sirt1激活可以缓解体内和体外的衰老，通过去乙酰化来稳定Foxo3并维持其转录活性。意义：高血糖通过Mettl3/Foxo3/Sirt1轴驱动干细胞衰老，从而破坏牙槽骨稳态，提示在糖尿病条件下进行再生治疗是一种有前景的治疗策略。

{"title":"Hyperglycemia disrupts alveolar bone homeostasis by inducing stem cell senescence through Mettl3/Foxo3/Sirt1 axis in diabetic periodontitis","authors":"Jie Zhou , Xinyue Li , Lanxi Xiao , Yanlin Zhu , Yuhan Yang , Xiang Gao","doi":"10.1016/j.lfs.2026.124215","DOIUrl":"10.1016/j.lfs.2026.124215","url":null,"abstract":"<div><h3>Aims</h3><div>Diabetes exacerbates periodontitis by intensifying inflammatory responses and impairing tissue regeneration. Hyperglycemia-induced dysfunction of jawbone-derived bone marrow mesenchymal stem cells (BMSCs) contributes to the imbalance of bone remodeling and periodontal homeostasis. This study aimed to reveal the role and regulatory mechanism of stem cell senescence in diabetic periodontitis.</div></div><div><h3>Materials and methods</h3><div>Diabetic periodontitis model was established in mice by high-fat diet, streptozotocin injections and ligation. Following treatment with high glucose (HG) and <em>Porphyromonas gingivalis</em> lipopolysaccharide (Pg-LPS), BMSCs were analyzed for cellular senescence and m<sup>6</sup>A levels. Functional roles of Mettl3, Foxo3, and Sirt1 were explored by knockdown, overexpression, and pharmacological activation. MeRIP, ChIP, and RNA stability assays were employed to explore m<sup>6</sup>A-dependent Foxo3 degradation and its interaction with Sirt1. Therapeutic potential of Sirt1 activation was validated in vivo.</div></div><div><h3>Key findings</h3><div>Diabetic mice developed alveolar bone degeneration and cellular senescence pathway enrichment. HG + LPS co-stimulation induced BMSCs senescence, elevated m<sup>6</sup>A levels and Mettl3 expression. Mettl3 knockdown reduced senescence-associated secretory phenotypes. Mechanistically, m<sup>6</sup>A hypermodification on the Foxo3 coding sequence accelerated mRNA decay and impeded nuclear translocation via Ythdf2 recognition. Through its transcriptional regulation of Sirt1, Foxo3 mitigated senescence when overexpressed and exacerbated oxidative damage when knocked down. Sirt1 activation alleviated senescence in vitro and in vivo, reciprocally stabilizing Foxo3 and maintaining its transcriptional activity via deacetylation.</div></div><div><h3>Significance</h3><div>Hyperglycemia disrupts alveolar bone homeostasis by driving stem cell senescence through the Mettl3/Foxo3/Sirt1 axis, suggesting a promising therapeutic strategy for regenerative therapy under diabetic conditions.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124215"},"PeriodicalIF":5.1,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011130","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}

引用次数: 0

Corrigendum to “SNHG8/miR-873-3p/CDK6 axis triggers proliferation and migration of smooth muscle cells in intimal hyperplasia” [Life Sci. 379 (2025) 123878] “SNHG8/miR-873-3p/CDK6轴触发内膜增生中平滑肌细胞的增殖和迁移”[生命科学379(2025)123878]。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-17 DOI: 10.1016/j.lfs.2026.124198

Jiaying Sun , Jing Qi , Jianyao Su , Jiye Wan

引用次数: 0

Aging-associated GSK3β overexpression exacerbates hepatic ischemia-reperfusion injury through Nrf2 deficiency-induced hepatocyte ferroptosis 衰老相关的GSK3β过表达通过Nrf2缺乏诱导的肝细胞铁凋亡加剧肝缺血再灌注损伤。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-16 DOI: 10.1016/j.lfs.2026.124214

You Wu , Yan Zhang , Shiwei Zhang , Huahong Yang , Xinxin Ci

Background and aims

Aging can exacerbate hepatic ischemia-reperfusion injury (HIRI), but the underlying mechanisms remain uncertain. In this study, the mechanisms through which age-related dysregulation of the GSK3β-Nrf2 axis promotes hepatocyte ferroptosis and exacerbates HIRI were investigated.

Methods

We used a comparative approach to analyze the following: 1) human liver specimens from young (25–35 years) and elderly (65–75 years) donors; 2) young and aged C57BL/6 mice and Nrf2-knockout (Nrf2-KO) mouse models subjected to HIRI; and 3) radiation-induced senescent L02 hepatocytes. Key interventions included the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the GSK3β inhibitor lithium (LiCl).

Results

Our study revealed that aging leads to significant downregulation of Nrf2 in human livers, aged mice, and senescent hepatocytes. This suppression of age-related Nrf2 exacerbates HIRI, as reflected by impaired antioxidant defenses and increased ferroptosis (elevated lipid peroxidation, iron overload, malondialdehyde (MDA) accumulation, glutathione (GSH) depletion and TFR upregulation). Genetic Nrf2 deficiency exacerbates these pathological changes in both cellular and animal models. Notably, treatment with Fer-1 effectively reduced liver damage biomarkers (ALT/AST) and ferroptotic responses in Nrf2-knockout systems. Mechanistically, aging-induced GSK3β overexpression drives Nrf2 dysfunction, establishing a GSK3β-Nrf2-ferroptosis axis involved in IRI progression. Notably, therapeutic targeting of GSK3β by microdose lithium or ferroptosis inhibition by Fer-1 alleviated HIRI in aged mice.

Conclusions

Our study revealed a novel aging-related pathogenesis axis in which GSK3β upregulation drives Nrf2 deficiency-mediated ferroptosis in hepatocytes, thereby exacerbating HIRI. Pharmacological targeting of this pathway may be a promising therapeutic strategy for elderly patients undergoing liver surgery.

背景与目的：衰老可加重肝缺血再灌注损伤（HIRI），但其机制尚不清楚。在本研究中，研究了GSK3β-Nrf2轴的年龄相关失调促进肝细胞铁凋亡和加重HIRI的机制。方法：采用比较方法分析：1)年轻（25-35 岁）和老年（65-75 岁）供者的肝脏标本；2) HIRI诱导的C57BL/6小鼠和nrf2敲除（Nrf2-KO）小鼠模型；3)辐射诱导的衰老L02肝细胞。主要干预措施包括给予铁下垂抑制剂铁抑素-1 （fer1）和GSK3β抑制剂锂（LiCl）。结果：我们的研究表明，衰老导致人类肝脏、老年小鼠和衰老肝细胞中Nrf2的显著下调。这种与年龄相关的Nrf2的抑制加剧了HIRI，反映在抗氧化防御受损和铁下沉增加（脂质过氧化升高、铁超载、丙二醛（MDA）积累、谷胱甘肽（GSH）消耗和TFR上调）。在细胞和动物模型中，遗传Nrf2缺乏加剧了这些病理变化。值得注意的是，在nrf2敲除系统中，用fe -1治疗可有效降低肝损伤生物标志物（ALT/AST）和铁致凋亡反应。从机制上讲，衰老诱导的GSK3β过表达驱动Nrf2功能障碍，建立参与IRI进展的GSK3β-Nrf2-铁下沉轴。值得注意的是，通过微剂量锂靶向GSK3β或fer1抑制铁下垂可减轻老年小鼠HIRI。结论：我们的研究揭示了一种新的与衰老相关的发病轴，其中GSK3β上调驱动Nrf2缺陷介导的肝细胞铁凋亡，从而加剧HIRI。这一途径的药理靶向可能是一种很有前途的治疗策略，用于老年肝脏手术患者。

{"title":"Aging-associated GSK3β overexpression exacerbates hepatic ischemia-reperfusion injury through Nrf2 deficiency-induced hepatocyte ferroptosis","authors":"You Wu , Yan Zhang , Shiwei Zhang , Huahong Yang , Xinxin Ci","doi":"10.1016/j.lfs.2026.124214","DOIUrl":"10.1016/j.lfs.2026.124214","url":null,"abstract":"<div><h3>Background and aims</h3><div>Aging can exacerbate hepatic ischemia-reperfusion injury (HIRI), but the underlying mechanisms remain uncertain. In this study, the mechanisms through which age-related dysregulation of the GSK3β-Nrf2 axis promotes hepatocyte ferroptosis and exacerbates HIRI were investigated.</div></div><div><h3>Methods</h3><div>We used a comparative approach to analyze the following: 1) human liver specimens from young (25–35 years) and elderly (65–75 years) donors; 2) young and aged C57BL/6 mice and Nrf2-knockout (Nrf2-KO) mouse models subjected to HIRI; and 3) radiation-induced senescent L02 hepatocytes. Key interventions included the administration of the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the GSK3β inhibitor lithium (LiCl).</div></div><div><h3>Results</h3><div>Our study revealed that aging leads to significant downregulation of Nrf2 in human livers, aged mice, and senescent hepatocytes. This suppression of age-related Nrf2 exacerbates HIRI, as reflected by impaired antioxidant defenses and increased ferroptosis (elevated lipid peroxidation, iron overload, malondialdehyde (MDA) accumulation, glutathione (GSH) depletion and TFR upregulation). Genetic Nrf2 deficiency exacerbates these pathological changes in both cellular and animal models. Notably, treatment with Fer-1 effectively reduced liver damage biomarkers (ALT/AST) and ferroptotic responses in Nrf2-knockout systems. Mechanistically, aging-induced GSK3β overexpression drives Nrf2 dysfunction, establishing a GSK3β-Nrf2-ferroptosis axis involved in IRI progression. Notably, therapeutic targeting of GSK3β by microdose lithium or ferroptosis inhibition by Fer-1 alleviated HIRI in aged mice.</div></div><div><h3>Conclusions</h3><div>Our study revealed a novel aging-related pathogenesis axis in which GSK3β upregulation drives Nrf2 deficiency-mediated ferroptosis in hepatocytes, thereby exacerbating HIRI. Pharmacological targeting of this pathway may be a promising therapeutic strategy for elderly patients undergoing liver surgery.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124214"},"PeriodicalIF":5.1,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998621","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}

引用次数: 0

Galectin-9 in human trophoblast cells: Implications for maternal-fetal immune balance and pregnancy complications 人滋养细胞中的半乳糖凝集素-9：对母胎免疫平衡和妊娠并发症的影响。

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-14 DOI: 10.1016/j.lfs.2025.124173

Xuqing He , Penghao Li , Jingliang Xu , Jingxian Zhang , Yungang Liu , Ju Huang , Xinrui Chi , Qiaoxin Zhang , Yanrong Chen , Jin Huang , Hui Wang , Zhengping Zhuang , Jiang Gu

Introduction

Galectin-9 (Gal-9) is a multifunctional protein belonging to the β-galactoside-binding lectin family playing crucial roles in immune regulation of tumor and pregnancy. However, its roles in placental pathophysiology such as preeclampsia have not been well understood. In this study the involvement of Gal-9 in trophoblast functioning and sustained immune balance were explored.

Methods

Immortalized human trophoblast cells (HTR-8/SVneo) were subjected to chemical hypoxia (induced by CoCl₂) and oxidative stress (induced by HMGB1), then treated with HIF-1α knockdown or specific inhibitors. Subsequently, Gal-9 and IgG4 (another newly established immune regulator of pregnancy) levels were analyzed with immunofluorescence assay and Western blotting, and in human placental tissues with immunohistochemistry; moreover, the invasiveness of HTR-8/SVneo cells co-cultured with peripheral blood mononuclear cells (PBMCs) was evaluated with transwell assay, and IgG4 determined with ELISA and Western blotting.

Results

Both chemical hypoxia and oxidative stress induced Gal-9 expression in HTR-8/SVneo cells, which were initiated by the elevation of HIF-1 and apoptosis signal-regulating kinase 1 (ASK1), respectively. Interestingly, IgG4 secretion from PBMCs co-cultured with HTR-8/SVneo was dependent on the duration of hypoxia: it was enhanced up to day 5 but inhibited by day 7, with persistent elevation of Gal-9 but apoptosis of PBMCs under prolonged hypoxia.

Conclusion

Hypoxia and oxidative stress upregulate trophoblast Gal-9 through distinct mechanisms. Hypoxia duration affects IgG4 production in co-cultures—enhanced short-term but suppressed long-term—implying pathological placental hypoxia may increase Gal-9, reduce IgG4, and disrupt maternal-fetal immune balance. This newly discovered regulatory pathway of Gal-9 in the placenta during pregnancy may contribute to the pathogenesis of pregnancy-associated diseases including PE.

半乳糖凝集素-9 （Galectin-9, Gal-9）是β-半乳糖结合凝集素家族的一种多功能蛋白，在肿瘤和妊娠的免疫调节中起重要作用。然而，它在胎盘病理生理中的作用，如先兆子痫尚未得到很好的理解。本研究探讨了Gal-9在滋养细胞功能和持续免疫平衡中的作用。方法：永生化人滋养细胞HTR-8/SVneo经化学缺氧（CoCl2诱导）和氧化应激（HMGB1诱导）处理，然后用HIF-1α下调或特异性抑制剂处理。随后，用免疫荧光法和Western blotting分析Gal-9和IgG4（另一种新建立的妊娠免疫调节剂）水平，并用免疫组织化学分析人胎盘组织中的Gal-9和IgG4水平；采用transwell法评价HTR-8/SVneo细胞与外周血单个核细胞（PBMCs）共培养的侵袭性，ELISA法和Western blotting法检测IgG4。结果：化学缺氧和氧化应激均可诱导HTR-8/SVneo细胞中Gal-9的表达，其表达分别由HIF-1和凋亡信号调节激酶1（凋亡信号调节激酶1）的升高引发。有趣的是，与HTR-8/SVneo共培养的PBMCs的IgG4分泌依赖于缺氧的持续时间：在第5天，IgG4分泌增强，但在第7天被抑制，在长时间缺氧下，Gal-9持续升高，但PBMCs凋亡。结论：缺氧和氧化应激通过不同的机制上调滋养细胞Gal-9。缺氧持续时间影响共培养中IgG4的产生-短期增强但长期抑制，这意味着病理性胎盘缺氧可能增加Gal-9，降低IgG4，并破坏母胎免疫平衡。这一新发现的妊娠期胎盘中Gal-9的调控通路可能参与妊娠相关疾病包括PE的发病机制。

{"title":"Galectin-9 in human trophoblast cells: Implications for maternal-fetal immune balance and pregnancy complications","authors":"Xuqing He , Penghao Li , Jingliang Xu , Jingxian Zhang , Yungang Liu , Ju Huang , Xinrui Chi , Qiaoxin Zhang , Yanrong Chen , Jin Huang , Hui Wang , Zhengping Zhuang , Jiang Gu","doi":"10.1016/j.lfs.2025.124173","DOIUrl":"10.1016/j.lfs.2025.124173","url":null,"abstract":"<div><h3>Introduction</h3><div>Galectin-9 (Gal-9) is a multifunctional protein belonging to the β-galactoside-binding lectin family playing crucial roles in immune regulation of tumor and pregnancy. However, its roles in placental pathophysiology such as preeclampsia have not been well understood. In this study the involvement of Gal-9 in trophoblast functioning and sustained immune balance were explored.</div></div><div><h3>Methods</h3><div>Immortalized human trophoblast cells (HTR-8/SVneo) were subjected to chemical hypoxia (induced by CoCl<sub>2</sub>) and oxidative stress (induced by HMGB1), then treated with HIF-1α knockdown or specific inhibitors. Subsequently, Gal-9 and IgG4 (another newly established immune regulator of pregnancy) levels were analyzed with immunofluorescence assay and Western blotting, and in human placental tissues with immunohistochemistry; moreover, the invasiveness of HTR-8/SVneo cells co-cultured with peripheral blood mononuclear cells (PBMCs) was evaluated with transwell assay, and IgG4 determined with ELISA and Western blotting.</div></div><div><h3>Results</h3><div>Both chemical hypoxia and oxidative stress induced Gal-9 expression in HTR-8/SVneo cells, which were initiated by the elevation of HIF-1 and apoptosis signal-regulating kinase 1 (ASK1), respectively. Interestingly, IgG4 secretion from PBMCs co-cultured with HTR-8/SVneo was dependent on the duration of hypoxia: it was enhanced up to day 5 but inhibited by day 7, with persistent elevation of Gal-9 but apoptosis of PBMCs under prolonged hypoxia.</div></div><div><h3>Conclusion</h3><div>Hypoxia and oxidative stress upregulate trophoblast Gal-9 through distinct mechanisms. Hypoxia duration affects IgG4 production in co-cultures—enhanced short-term but suppressed long-term—implying pathological placental hypoxia may increase Gal-9, reduce IgG4, and disrupt maternal-fetal immune balance. This newly discovered regulatory pathway of Gal-9 in the placenta during pregnancy may contribute to the pathogenesis of pregnancy-associated diseases including PE.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124173"},"PeriodicalIF":5.1,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989981","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}

引用次数: 0

iNKT cell activation exacerbates isoproterenol-induced cardiac injury through macrophage IFN-γ–STAT1 signaling iNKT细胞激活通过巨噬细胞IFN -γ-STAT1信号通路加重异丙肾上腺素诱导的心脏损伤

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-13 DOI: 10.1016/j.lfs.2026.124212

Laiping Zhang , Jie Liu , Xiao Guan , Boshi Liu , Ying Liu , Weinian Shou , Xin Chen , Xiaohui Li , Dayan Cao

Aims

With the extensive application of immunotherapy in treating cancer, the immunotherapy-related cardiovascular toxicity (ITR-CVT) has gotten a rapid recognition due to its high mortality. Previously, we have found that potential cancer immunotherapies based on promoting iNKT cell activation exacerbate ISO-induced cardiac injury, but the underlying mechanism is unknown. The current study is to determine which specific cell type/s and the corresponding molecular pathways are responsible for such a cardiotoxicity.

Materials and methods

Transcriptome sequencing and bioinformatic analysis were performed on heart tissues from an enhanced cardiac injury model following iNKT cell activation via α-Galactosylceramide (αGC). The role of IFN-γ–STAT1 signaling was validated using IFN-γ antibody blocking and JAK-STAT1 chemical inhibition. The experiments of Macrophage isolation and depletion were conducted to assess cell-specific contributions. In vitro co-culture experiments with αGC-primed macrophages and fibroblasts were conducted under STAT1 inhibition or silencing. Tumor-bearing mice were also examined.

Key findings

Transcriptome analysis identified IFN-γ–STAT1 signaling as central to the enhanced cardiac injury, blocking IFN-γ or inhibiting STAT1 could attenuate the injury. Macrophages were identified as the main source of IFN-γ–STAT1 activation, and their depletion significantly reversed cardiac injury exacerbation. In vitro, STAT1 inhibition or silencing reduced fibroblast activation induced by αGC-primed macrophages. In tumor-bearing mice, αGC also further exacerbated cardiac injury.

Significance

These findings revealed that the activation of STAT1 in cardiac macrophages via IFNγ critically contributes to cardiotoxicity induced by iNKT-immunotherapy, which provides a potential method to manage ITR-CVT in patients.

随着免疫治疗在肿瘤治疗中的广泛应用，免疫治疗相关心血管毒性（ITR-CVT）因其高致死率而得到了迅速的认识。先前，我们发现基于促进iNKT细胞活化的潜在癌症免疫疗法会加剧iso诱导的心脏损伤，但其潜在机制尚不清楚。目前的研究是确定哪种特定的细胞类型和相应的分子途径是造成这种心脏毒性的原因。材料和方法采用α-半乳糖神经酰胺（αGC）激活iNKT细胞后，对增强心脏损伤模型的心脏组织进行转录组测序和生物信息学分析。IFN-γ抗体阻断和JAK-STAT1化学抑制验证了IFN-γ - stat1信号通路的作用。通过巨噬细胞分离和消耗实验来评估细胞特异性贡献。在STAT1抑制或沉默的情况下，进行α gc引物巨噬细胞和成纤维细胞的体外共培养实验。对荷瘤小鼠也进行了检查。转录组分析发现IFN-γ - STAT1信号是心脏损伤增强的核心，阻断IFN-γ或抑制STAT1可减轻心脏损伤。巨噬细胞被认为是IFN -γ-STAT1激活的主要来源，巨噬细胞的消耗可以显著逆转心脏损伤加剧。体外，STAT1抑制或沉默可降低α gc引发的巨噬细胞诱导的成纤维细胞活化。在荷瘤小鼠中，αGC也进一步加重了心脏损伤。这些发现表明，通过IFNγ激活心脏巨噬细胞中的STAT1对inkt免疫治疗诱导的心脏毒性至关重要，这为治疗ITR-CVT患者提供了一种潜在的方法。

{"title":"iNKT cell activation exacerbates isoproterenol-induced cardiac injury through macrophage IFN-γ–STAT1 signaling","authors":"Laiping Zhang , Jie Liu , Xiao Guan , Boshi Liu , Ying Liu , Weinian Shou , Xin Chen , Xiaohui Li , Dayan Cao","doi":"10.1016/j.lfs.2026.124212","DOIUrl":"10.1016/j.lfs.2026.124212","url":null,"abstract":"<div><h3>Aims</h3><div>With the extensive application of immunotherapy in treating cancer, the immunotherapy-related cardiovascular toxicity (ITR-CVT) has gotten a rapid recognition due to its high mortality. Previously, we have found that potential cancer immunotherapies based on promoting iNKT cell activation exacerbate ISO-induced cardiac injury, but the underlying mechanism is unknown. The current study is to determine which specific cell type/s and the corresponding molecular pathways are responsible for such a cardiotoxicity.</div></div><div><h3>Materials and methods</h3><div>Transcriptome sequencing and bioinformatic analysis were performed on heart tissues from an enhanced cardiac injury model following iNKT cell activation via α-Galactosylceramide (αGC). The role of IFN-γ–STAT1 signaling was validated using IFN-γ antibody blocking and JAK-STAT1 chemical inhibition. The experiments of Macrophage isolation and depletion were conducted to assess cell-specific contributions. In vitro co-culture experiments with αGC-primed macrophages and fibroblasts were conducted under STAT1 inhibition or silencing. Tumor-bearing mice were also examined.</div></div><div><h3>Key findings</h3><div>Transcriptome analysis identified IFN-γ–STAT1 signaling as central to the enhanced cardiac injury, blocking IFN-γ or inhibiting STAT1 could attenuate the injury. Macrophages were identified as the main source of IFN-γ–STAT1 activation, and their depletion significantly reversed cardiac injury exacerbation. In vitro, STAT1 inhibition or silencing reduced fibroblast activation induced by αGC-primed macrophages. In tumor-bearing mice, αGC also further exacerbated cardiac injury.</div></div><div><h3>Significance</h3><div>These findings revealed that the activation of STAT1 in cardiac macrophages via IFNγ critically contributes to cardiotoxicity induced by iNKT-immunotherapy, which provides a potential method to manage ITR-CVT in patients.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124212"},"PeriodicalIF":5.1,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981654","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}

引用次数: 0

Single-cell RNA sequencing reveals the role of neutrophils in intestinal ischemia-reperfusion injury in mice 单细胞RNA测序揭示了中性粒细胞在小鼠肠缺血再灌注损伤中的作用

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-13 DOI: 10.1016/j.lfs.2026.124208

Ran Li , Ao Wang , Jiayi Cao , Kehui Li , Hao Zhang , Yiwen Wang , Simiao Chen , Mengmeng Zhuang , Chao Meng , Wensheng Wang , Yong Sun

Objective

Intestinal ischemia-reperfusion injury (IRI) severely compromises the mucosal barrier. While neutrophils are key responders, their specific roles and mechanisms remain unclear. This study aims to delineate the functional heterogeneity of neutrophils in intestinal IRI and identify the underlying molecular pathways.

Methods

A murine model of intestinal IRI was established by subjecting C57BL/6 mice to 45 min of ischemia and 4 h of reperfusion. Single-cell RNA sequencing (scRNA-seq) was performed on intestinal tissues. Neutrophil depletion, co-culture assays, and pharmacological modulation of endoplasmic reticulum stress (ERS) were employed for functional validation.

Results

scRNA-seq analysis revealed a significant expansion of neutrophils and inflammatory monocytes alongside a reduction in lymphocytes post-IRI. Notably, we identified a distinct pro-inflammatory neutrophil subcluster (C5), characterized by high expression of Atf4 and ERS-related genes. In vivo neutrophil depletion markedly alleviated intestinal damage, evidenced by improved histology, reduced serum DAO and IL-6 levels, and preserved Occludin expression. Mechanistically, neutrophils were shown to exacerbate injury via the ERS pathway. Pharmacological induction (tunicamycin) or inhibition (4-PBA) of ERS significantly augmented or mitigated IRI severity, respectively, with ATF4 playing a central role.

Conclusion

This study identifies a pathogenic neutrophil subpopulation that drives intestinal IRI through the ATF4-mediated ERS pathway. These findings provide new insights into the immunopathology of IRI and highlight ATF4 or specific neutrophil subsets as potential therapeutic targets for mitigating intestinal damage.

目的肠缺血再灌注损伤（IRI）严重损害粘膜屏障。虽然中性粒细胞是关键的应答者，但它们的具体作用和机制尚不清楚。本研究旨在描述中性粒细胞在肠道IRI中的功能异质性，并确定其潜在的分子途径。方法C57BL/6小鼠缺血45 min，再灌注4 h，建立小鼠肠IRI模型。对肠组织进行单细胞RNA测序（scRNA-seq）。中性粒细胞耗竭、共培养试验和内质网应激（ERS）的药理调节被用于功能验证。结果scrna -seq分析显示，iri后中性粒细胞和炎症单核细胞显著增加，淋巴细胞减少。值得注意的是，我们发现了一个独特的促炎中性粒细胞亚群（C5），其特征是Atf4和ers相关基因的高表达。体内中性粒细胞耗竭明显减轻肠道损伤，组织学改善，血清DAO和IL-6水平降低，Occludin表达保持不变。从机制上讲，中性粒细胞通过ERS通路加重损伤。药物诱导（tunicamycin）或抑制（4-PBA）分别显著增强或减轻IRI严重程度，其中ATF4起核心作用。本研究确定了一个致病中性粒细胞亚群，该亚群通过atf4介导的ERS途径驱动肠道IRI。这些发现为IRI的免疫病理学提供了新的见解，并突出了ATF4或特定中性粒细胞亚群作为减轻肠道损伤的潜在治疗靶点。

{"title":"Single-cell RNA sequencing reveals the role of neutrophils in intestinal ischemia-reperfusion injury in mice","authors":"Ran Li , Ao Wang , Jiayi Cao , Kehui Li , Hao Zhang , Yiwen Wang , Simiao Chen , Mengmeng Zhuang , Chao Meng , Wensheng Wang , Yong Sun","doi":"10.1016/j.lfs.2026.124208","DOIUrl":"10.1016/j.lfs.2026.124208","url":null,"abstract":"<div><h3>Objective</h3><div>Intestinal ischemia-reperfusion injury (IRI) severely compromises the mucosal barrier. While neutrophils are key responders, their specific roles and mechanisms remain unclear. This study aims to delineate the functional heterogeneity of neutrophils in intestinal IRI and identify the underlying molecular pathways.</div></div><div><h3>Methods</h3><div>A murine model of intestinal IRI was established by subjecting C57BL/6 mice to 45 min of ischemia and 4 h of reperfusion. Single-cell RNA sequencing (scRNA-seq) was performed on intestinal tissues. Neutrophil depletion, co-culture assays, and pharmacological modulation of endoplasmic reticulum stress (ERS) were employed for functional validation.</div></div><div><h3>Results</h3><div>scRNA-seq analysis revealed a significant expansion of neutrophils and inflammatory monocytes alongside a reduction in lymphocytes post-IRI. Notably, we identified a distinct pro-inflammatory neutrophil subcluster (C5), characterized by high expression of Atf4 and ERS-related genes. In vivo neutrophil depletion markedly alleviated intestinal damage, evidenced by improved histology, reduced serum DAO and IL-6 levels, and preserved Occludin expression. Mechanistically, neutrophils were shown to exacerbate injury via the ERS pathway. Pharmacological induction (tunicamycin) or inhibition (4-PBA) of ERS significantly augmented or mitigated IRI severity, respectively, with ATF4 playing a central role.</div></div><div><h3>Conclusion</h3><div>This study identifies a pathogenic neutrophil subpopulation that drives intestinal IRI through the ATF4-mediated ERS pathway. These findings provide new insights into the immunopathology of IRI and highlight ATF4 or specific neutrophil subsets as potential therapeutic targets for mitigating intestinal damage.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124208"},"PeriodicalIF":5.1,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981655","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}

引用次数: 0

From inflammation to innovation: Exploring the emerging roles of itaconate in ARDS 从炎症到创新：探索衣康酸在ARDS中的新作用

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-12 DOI: 10.1016/j.lfs.2026.124209

Guixiang Yang , Ling Hu , Min Zhong , Xia Huang , Jianhua Li

Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure characterized by diffuse alveolar damage, pulmonary edema, and decreased lung compliance. It represents the most severe manifestation of acute lung injury (ALI). Conditions such as sepsis, acute pancreatitis, and trauma are well-recognized triggers of ALI/ARDS. Given the high mortality rate and limited therapeutic options, current management strategies primarily rely on lung-protective ventilation, careful fluid management, and pharmacological interventions. Consequently, there is an urgent need to develop novel and more effective therapeutic approaches. Itaconate, a metabolite generated during immune cell activation, exhibits potent anti-inflammatory and antioxidant properties. Emerging evidence suggests that itaconate confers protective effects in various inflammatory diseases. This review explores the mechanisms and functions of itaconate in the context of ARDS, providing new insights into its potential as a therapeutic agent.

急性呼吸窘迫综合征（ARDS）是一种危及生命的呼吸衰竭形式，其特征是弥漫性肺泡损伤、肺水肿和肺顺应性下降。它是急性肺损伤（ALI）最严重的表现。脓毒症、急性胰腺炎和创伤等疾病是公认的ALI/ARDS诱因。鉴于高死亡率和有限的治疗选择，目前的管理策略主要依赖于肺保护性通气、仔细的液体管理和药物干预。因此，迫切需要开发新的和更有效的治疗方法。衣康酸是免疫细胞激活过程中产生的代谢物，具有有效的抗炎和抗氧化特性。新出现的证据表明衣康酸对各种炎症性疾病具有保护作用。本文综述了衣康酸在ARDS中的作用机制和功能，为其作为治疗药物的潜力提供了新的见解。

引用次数: 0

Pulmonary neuroendocrine cell as a therapeutic strategy in pulmonary hypertension: Great expectations or Bleak House? 肺神经内分泌细胞作为肺动脉高压的治疗策略：远大的期望还是荒凉的房子？

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Life sciences

Pub Date : 2026-01-12 DOI: 10.1016/j.lfs.2026.124194

Yunhua Yang , Yurong Zhang , Shaoxin Gong , Na Liang , Nanping Li , Gangkai Tan , Xiaoyong Lei , Aiping Wang

Pulmonary hypertension (PH) is a cardiovascular disease with a poor prognosis, mainly attributed to irreversible pulmonary vascular remodeling. Although there are already mature clinical diagnosis and treatment guidelines, the mortality rate of PH remains unacceptably high, highlighting the urgent need for innovative treatment strategies. Pulmonary neuroendocrine cells (PNECs) are rare pulmonary epithelial cells distributed in the airways and have physiological functions such as regulating chemical sensation and tissue repair. The proliferation phenomenon of PNECs in chronic lung diseases, notably COPD and asthma, as well as its identity as a progenitor cell of lung neuroendocrine carcinoma, jointly emphasize the therapeutic potential of targeting PNECs. Emerging evidence indicates that PNECs can regulate the tension of micro vessels around the bronchioles through paracrine neuropeptide signaling and lead to vascular pathological remodeling, making it a potential therapeutic target for PH. This review systematically describes the pathophysiological contribution of PNECs to PH development, with particular attention to the homeostasis regulation of pulmonary vascular wall cells such as pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) by their paracrine bioactive substances. We further explored the therapeutic strategies and challenges of regulating pulmonary vascular remodeling driven by PNECs, with the expectation of achieving precise PH management.

肺动脉高压（Pulmonary hypertension， PH）是一种预后较差的心血管疾病，其主要原因是肺血管的不可逆重构。虽然已有成熟的临床诊断和治疗指南，但PH的死亡率仍然高得令人无法接受，因此迫切需要创新的治疗策略。肺神经内分泌细胞（Pulmonary neuroendocrine cells, PNECs）是一种罕见的肺上皮细胞，分布在气道中，具有调节化学感觉和组织修复等生理功能。PNECs在慢性肺部疾病，特别是COPD和哮喘中的增殖现象，以及其作为肺神经内分泌癌祖细胞的身份，共同强调了靶向PNECs的治疗潜力。越来越多的证据表明，PNECs可以通过旁分泌神经肽信号调节细支气管周围微血管的张力，导致血管的病理重塑，使其成为PH的潜在治疗靶点。本文系统地介绍了PNECs对PH发展的病理生理贡献。特别关注肺动脉内皮细胞（PAECs）和肺动脉平滑肌细胞（PASMCs）等肺血管壁细胞通过其旁分泌生物活性物质的稳态调节。我们进一步探讨了由PNECs驱动的肺血管重塑调节的治疗策略和挑战，期望实现精确的PH管理。

{"title":"Pulmonary neuroendocrine cell as a therapeutic strategy in pulmonary hypertension: Great expectations or Bleak House?","authors":"Yunhua Yang , Yurong Zhang , Shaoxin Gong , Na Liang , Nanping Li , Gangkai Tan , Xiaoyong Lei , Aiping Wang","doi":"10.1016/j.lfs.2026.124194","DOIUrl":"10.1016/j.lfs.2026.124194","url":null,"abstract":"<div><div>Pulmonary hypertension (PH) is a cardiovascular disease with a poor prognosis, mainly attributed to irreversible pulmonary vascular remodeling. Although there are already mature clinical diagnosis and treatment guidelines, the mortality rate of PH remains unacceptably high, highlighting the urgent need for innovative treatment strategies. Pulmonary neuroendocrine cells (PNECs) are rare pulmonary epithelial cells distributed in the airways and have physiological functions such as regulating chemical sensation and tissue repair. The proliferation phenomenon of PNECs in chronic lung diseases, notably COPD and asthma, as well as its identity as a progenitor cell of lung neuroendocrine carcinoma, jointly emphasize the therapeutic potential of targeting PNECs. Emerging evidence indicates that PNECs can regulate the tension of micro vessels around the bronchioles through paracrine neuropeptide signaling and lead to vascular pathological remodeling, making it a potential therapeutic target for PH. This review systematically describes the pathophysiological contribution of PNECs to PH development, with particular attention to the homeostasis regulation of pulmonary vascular wall cells such as pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) by their paracrine bioactive substances. We further explored the therapeutic strategies and challenges of regulating pulmonary vascular remodeling driven by PNECs, with the expectation of achieving precise PH management.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"388 ","pages":"Article 124194"},"PeriodicalIF":5.1,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145981651","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}

引用次数: 0