Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.phrs.2026.108122
Xue Wu , Xia Du , Chenxi Lu
Cardiovascular Disease (CVDs), as a major life-threatening disease, has attracted worldwide attention. Seeking novel and effective therapeutic strategies is still among the important in the cardiovascular field. Forkhead box O (FoxO) family comprises a group of transcription factors with highly conserved structures that have a major role in a plethora of biological functions. Recently, a considerable amount of research has shown the physiological and pathological roles of Fox family (especially FoxO1) in CVDs (including myocardial ischemia-reperfusion injury, myocardial hypertrophy, myocardial infarction, myocardial fibrosis, cardiomyopathy, and atherosclerosis), and they affect the plasticity, stress response, and metabolism of the heart by regulating various signaling pathways and biological functions. In this review, we outline the structure of the Fox family and FoxO1. Next, we summarize the various pathological and physiological mechanisms of FoxO1 (inflammation, oxidative stress, autophagy, endothelial dysfunction, lipid metabolism and angiogenesis), as well as the regulatory style of FoxO1 (phosphorylation, methylation, ubiquitination and acetylation). Finally, we also reviewe the latest research advancements and potential future research directions concerning FoxO1 regulators in CVDs, laying the foundation for its transformation into a new and powerful clinical application.
{"title":"Targeting FoxO1 in cardiovascular diseases: Mechanisms and therapeutic potential","authors":"Xue Wu , Xia Du , Chenxi Lu","doi":"10.1016/j.phrs.2026.108122","DOIUrl":"10.1016/j.phrs.2026.108122","url":null,"abstract":"<div><div>Cardiovascular Disease (CVDs), as a major life-threatening disease, has attracted worldwide attention. Seeking novel and effective therapeutic strategies is still among the important in the cardiovascular field. Forkhead box O (FoxO) family comprises a group of transcription factors with highly conserved structures that have a major role in a plethora of biological functions. Recently, a considerable amount of research has shown the physiological and pathological roles of Fox family (especially FoxO1) in CVDs (including myocardial ischemia-reperfusion injury, myocardial hypertrophy, myocardial infarction, myocardial fibrosis, cardiomyopathy, and atherosclerosis), and they affect the plasticity, stress response, and metabolism of the heart by regulating various signaling pathways and biological functions. In this review, we outline the structure of the Fox family and FoxO1. Next, we summarize the various pathological and physiological mechanisms of FoxO1 (inflammation, oxidative stress, autophagy, endothelial dysfunction, lipid metabolism and angiogenesis), as well as the regulatory style of FoxO1 (phosphorylation, methylation, ubiquitination and acetylation). Finally, we also reviewe the latest research advancements and potential future research directions concerning FoxO1 regulators in CVDs, laying the foundation for its transformation into a new and powerful clinical application.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108122"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097490","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}
Resveratrol (RESV) is a naturally occurring polyphenol with well-established antioxidant and anti-inflammatory properties, supporting its therapeutic potential in chronic respiratory diseases such as asthma. To enhance its efficacy, we developed a hybrid compound, R-TBZ, in which RESV is chemically linked to 4-hydroxythiobenzamide (TBZ), a slow-releasing hydrogen sulfide (H₂S) donor. This design aimed to improve chemical stability, bioavailability, and controlled activation while minimizing the toxicity associated with fast H₂S release. R-TBZ was synthesized via esterification of RESV with TBZ and showed high chemical stability, remaining over 95 % intact after 24 h under neutral and acidic conditions. Enzymatic hydrolysis occurred gradually (t₁/₂ ≈ 20 h), releasing RESV as the sole detectable product. In allergen-challenged bronchial epithelial cells, R-TBZ demonstrated superior efficacy compared with RESV or TBZ alone. It enhanced mitochondrial antioxidant defenses, reduced mucus production, and suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). R-TBZ inhibited allergen-induced epithelial–mesenchymal transition and TGF-β–induced fibroblast activation, reducing α-SMA and vimentin expression more effectively than the parent compounds, indicating synergistic anti-remodeling activity. In a murine model of allergic asthma, R-TBZ improved lung function, reduced airway hyperresponsiveness, restored β₂-agonist responsiveness, and attenuated eosinophilic inflammation, Th2 cytokine production, and plasma IgE levels. Importantly, R-TBZ reversed airway structural remodeling, reducing peribronchial α-SMA expression and preserving epithelial and goblet cell morphology, effects not fully achieved by RESV alone. Overall, R-TBZ combines dual anti-inflammatory and anti-remodeling activities, overcoming key limitations of RESV and H₂S donors. This hybrid represents a promising multi-target therapeutic strategy for asthma, particularly for steroid-resistant airway remodeling.
{"title":"A resveratrol–hydrogen sulfide donor hybrid as a multi-target therapeutic strategy for allergic asthma","authors":"Martina Simonelli , Ida Cerqua , Danilo D’Avino , Elisabetta Granato , Alessandra Perrella , Sara Perna , Antonietta Rossi , Raffaele Capasso , Federica Sodano , Antonia Scognamiglio , Elisa Magli , Ferdinando Fiorino , Giuseppe Caliendo , Beatrice Severino , Angela Corvino , Fiorentina Roviezzo","doi":"10.1016/j.phrs.2026.108121","DOIUrl":"10.1016/j.phrs.2026.108121","url":null,"abstract":"<div><div>Resveratrol (RESV) is a naturally occurring polyphenol with well-established antioxidant and anti-inflammatory properties, supporting its therapeutic potential in chronic respiratory diseases such as asthma. To enhance its efficacy, we developed a hybrid compound, R-TBZ, in which RESV is chemically linked to 4-hydroxythiobenzamide (TBZ), a slow-releasing hydrogen sulfide (H₂S) donor. This design aimed to improve chemical stability, bioavailability, and controlled activation while minimizing the toxicity associated with fast H₂S release. R-TBZ was synthesized via esterification of RESV with TBZ and showed high chemical stability, remaining over 95 % intact after 24 h under neutral and acidic conditions. Enzymatic hydrolysis occurred gradually (t₁/₂ ≈ 20 h), releasing RESV as the sole detectable product. In allergen-challenged bronchial epithelial cells, R-TBZ demonstrated superior efficacy compared with RESV or TBZ alone. It enhanced mitochondrial antioxidant defenses, reduced mucus production, and suppressed pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). R-TBZ inhibited allergen-induced epithelial–mesenchymal transition and TGF-β–induced fibroblast activation, reducing α-SMA and vimentin expression more effectively than the parent compounds, indicating synergistic anti-remodeling activity. In a murine model of allergic asthma, R-TBZ improved lung function, reduced airway hyperresponsiveness, restored β₂-agonist responsiveness, and attenuated eosinophilic inflammation, Th2 cytokine production, and plasma IgE levels. Importantly, R-TBZ reversed airway structural remodeling, reducing peribronchial α-SMA expression and preserving epithelial and goblet cell morphology, effects not fully achieved by RESV alone. Overall, R-TBZ combines dual anti-inflammatory and anti-remodeling activities, overcoming key limitations of RESV and H₂S donors. This hybrid represents a promising multi-target therapeutic strategy for asthma, particularly for steroid-resistant airway remodeling.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108121"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097463","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}
Pub Date : 2026-03-01Epub Date: 2026-02-12DOI: 10.1016/j.phrs.2026.108119
Mengli Wang , Honglan Yang , Zhongzheng Li , Sen Zeng , Ke Xu , Binghao Wang , Yongzhi Xie , Qingping Wang , Zhuolin Su , Mingri Zhao , Yiti Zhang , Mujun Liu , Beisha Tang , Xionghao Liu , Ruxu Zhang
{"title":"Corrigendum to “Impaired PARP1-dependent DNA repair in MORC2 mutations drives axonal degeneration in Charcot-Marie-Tooth disease subtype 2Z and spinal muscular atrophy-like neuromotor disorders” [Pharmacol. Res. 224 (2026) 108103]","authors":"Mengli Wang , Honglan Yang , Zhongzheng Li , Sen Zeng , Ke Xu , Binghao Wang , Yongzhi Xie , Qingping Wang , Zhuolin Su , Mingri Zhao , Yiti Zhang , Mujun Liu , Beisha Tang , Xionghao Liu , Ruxu Zhang","doi":"10.1016/j.phrs.2026.108119","DOIUrl":"10.1016/j.phrs.2026.108119","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108119"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195413","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}
Pub Date : 2026-03-01Epub Date: 2026-02-14DOI: 10.1016/j.phrs.2026.108138
Dong Dai , Xin Gao , Siqi Zhang , Hongyi Huang , Kun Wang , Jianjing Liu , Xingkai Wang , Yuan Miao , Zongxiao Liu , Panfeng Li , Qingshuang Lu , Shuo Jiang , Xueyao Chen , Licheng Yang , Yiliang Li , Rui Wang , Yingzi Zhang , Kuan Hu
PSMA-targeted radiopharmaceuticals have substantially advanced the management of prostate cancer; however, high nonspecific uptake in organs such as salivary glands and kidneys remains a clinical challenge. In our previous studies, incorporation of non-canonical amino acid linkers was shown to reduce off-target uptake while preserving or even enhancing tumor accumulation of PSMA-targeted radiotracers. Here, we present a first-in-human head-to-head comparison in which each of four linker-optimized PSMA radiotracers—[68Ga]Ga-PSMA-HK4, [68Ga]Ga-PSMA-HK7, [68Ga]Ga-PSMA-Y55, and [68Ga]Ga-PSMA-Y81—was individually compared with either [68Ga]Ga-PSMA-617 or [68Ga]Ga-PSMA-11, evaluating their in vivo pharmacokinetics and diagnostic performance in eight prostate cancer patients. Preclinical data demonstrated that all four radiotracers achieved comparable or enhanced tumor uptake, with [68Ga]Ga-PSMA-Y55 and [68Ga]Ga-PSMA-Y81 showing reduced renal accumulation relative to [68Ga]Ga-PSMA-617. Clinically, [68Ga]Ga-PSMA-HK4 and [68Ga]Ga-PSMA-HK7 exhibited lower salivary gland uptake, whereas [68Ga]Ga-PSMA-Y55 and [68Ga]Ga-PSMA-Y81 showed decreased renal retention compared with reference tracers. Tumor uptake of [68Ga]Ga-PSMA-HK4 and [68Ga]Ga-PSMA-Y55 was comparable to [68Ga]Ga-PSMA-617, while [68Ga]Ga-PSMA-HK7 and [68Ga]Ga-PSMA-Y81 displayed prolonged blood pool and cardiac retention. These clinical findings indicate that β3-amino acid linkers effectively reduced salivary gland uptake, while linker stereochemistry modulated renal clearance of PSMA radiotracers. Even subtle atomic-level linker variations resulted in substantial preclinical and clinical pharmacokinetic divergence, highlighting the necessity of precise molecular engineering in PSMA radiopharmaceuticals to achieve an improved tumor therapeutic index while reducing nonspecific toxicity.
靶向psma的放射性药物极大地促进了前列腺癌的治疗；然而，唾液腺和肾脏等器官的高非特异性摄取仍然是一个临床挑战。在先前的研究中，非规范氨基酸连接体的掺入被证明可以减少脱靶摄取，同时保持甚至增强psma靶向放射性示踪剂的肿瘤积累。本文以[68Ga]Ga-PSMA-617或[68Ga]Ga-PSMA-11为对照，首次对四种经连接剂优化的PSMA放射性示踪剂[68Ga]Ga-PSMA-HK4、[68Ga]Ga-PSMA-HK7、[68Ga]Ga-PSMA-Y55和[68Ga] ga -PSMA- y81在8例前列腺癌患者体内的药代动力学和诊断性能进行了对比研究。临床前数据表明，所有四种放射性示踪剂均达到相当或增强的肿瘤摄取，与[68Ga]Ga-PSMA-617相比，[68Ga]Ga-PSMA-Y55和[68Ga]Ga-PSMA-Y81显示肾脏积聚减少。在临床上，[68Ga]Ga-PSMA-HK4和[68Ga]Ga-PSMA-HK7表现出较低的唾液腺摄取，而与参考示踪剂相比，[68Ga]Ga-PSMA-Y55和[68Ga]Ga-PSMA-Y81表现出较低的肾潴留。[68Ga]Ga-PSMA-HK4和[68Ga]Ga-PSMA-Y55的肿瘤摄取与[68Ga]Ga-PSMA-617相当，而[68Ga]Ga-PSMA-HK7和[68Ga]Ga-PSMA-Y81表现为血池延长和心脏潴留。这些发现表明，β3-氨基酸连接物可有效减少唾液腺的摄取，而连接物立体化学可调节PSMA放射性示踪剂的肾脏清除。即使是微小的原子水平的连接体变异也会导致临床前和临床药代动力学的巨大差异，这突出了精确分子工程在PSMA放射性药物中实现提高肿瘤治疗指数同时降低非特异性毒性的必要性。
{"title":"First-in-human evaluation of four novel PSMA-targeted PET radiotracers with non-canonical amino acid linkage: A comparative study","authors":"Dong Dai , Xin Gao , Siqi Zhang , Hongyi Huang , Kun Wang , Jianjing Liu , Xingkai Wang , Yuan Miao , Zongxiao Liu , Panfeng Li , Qingshuang Lu , Shuo Jiang , Xueyao Chen , Licheng Yang , Yiliang Li , Rui Wang , Yingzi Zhang , Kuan Hu","doi":"10.1016/j.phrs.2026.108138","DOIUrl":"10.1016/j.phrs.2026.108138","url":null,"abstract":"<div><div>PSMA-targeted radiopharmaceuticals have substantially advanced the management of prostate cancer; however, high nonspecific uptake in organs such as salivary glands and kidneys remains a clinical challenge. In our previous studies, incorporation of non-canonical amino acid linkers was shown to reduce off-target uptake while preserving or even enhancing tumor accumulation of PSMA-targeted radiotracers. Here, we present a first-in-human head-to-head comparison in which each of four linker-optimized PSMA radiotracers—[<sup>68</sup>Ga]Ga-PSMA-HK4, [<sup>68</sup>Ga]Ga-PSMA-HK7, [<sup>68</sup>Ga]Ga-PSMA-Y55, and [<sup>68</sup>Ga]Ga-PSMA-Y81—was individually compared with either [<sup>68</sup>Ga]Ga-PSMA-617 or [<sup>68</sup>Ga]Ga-PSMA-11, evaluating their <em>in vivo</em> pharmacokinetics and diagnostic performance in eight prostate cancer patients. Preclinical data demonstrated that all four radiotracers achieved comparable or enhanced tumor uptake, with [<sup>68</sup>Ga]Ga-PSMA-Y55 and [<sup>68</sup>Ga]Ga-PSMA-Y81 showing reduced renal accumulation relative to [<sup>68</sup>Ga]Ga-PSMA-617. Clinically, [<sup>68</sup>Ga]Ga-PSMA-HK4 and [<sup>68</sup>Ga]Ga-PSMA-HK7 exhibited lower salivary gland uptake, whereas [<sup>68</sup>Ga]Ga-PSMA-Y55 and [<sup>68</sup>Ga]Ga-PSMA-Y81 showed decreased renal retention compared with reference tracers. Tumor uptake of [<sup>68</sup>Ga]Ga-PSMA-HK4 and [<sup>68</sup>Ga]Ga-PSMA-Y55 was comparable to [<sup>68</sup>Ga]Ga-PSMA-617, while [<sup>68</sup>Ga]Ga-PSMA-HK7 and [<sup>68</sup>Ga]Ga-PSMA-Y81 displayed prolonged blood pool and cardiac retention. These clinical findings indicate that β<sup>3</sup>-amino acid linkers effectively reduced salivary gland uptake, while linker stereochemistry modulated renal clearance of PSMA radiotracers. Even subtle atomic-level linker variations resulted in substantial preclinical and clinical pharmacokinetic divergence, highlighting the necessity of precise molecular engineering in PSMA radiopharmaceuticals to achieve an improved tumor therapeutic index while reducing nonspecific toxicity.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108138"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146207120","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}
Pub Date : 2026-03-01Epub Date: 2026-02-24DOI: 10.1016/j.phrs.2026.108152
Xianjiao Liu , Yanyan Wang , Andrea Abreo Medina , Dandan Liu , Jinyan Liu , Wenxuan Tang , Mengmeng Wang , Xingxiang Chen , Kehe Huang , Min Liu , Chunfeng Wang , Yunhuan Liu
Gut-liver axis disturbance is the unifying pathogenesis of cholestatic liver diseases. The purpose of this study was to explore the underlying mechanisms of the probiotic Lactobacillus amylovorus (LA) and its secreted extracellular vesicles (EVs) on liver damage and fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed and multidrug resistance protein 2 knockout (Mdr2-/-) mice. Direct replenishment of LA is sufficient to correct the DDC-fed and Mdr2-/--induced liver damage and fibrosis. Mechanistic studies show that the secretion of EVs is required for the LA-induced liver protective effects. RNA sequencing results demonstrated that the enrichment of differentially expressed genes was associated with glutathione metabolism, microbial metabolism in diverse environments and inflammatory mediator regulation of TRP channels in DDC-fed mice. Our findings revealed that LAEVs reshaped the gut microbiota, which was associated with increased bile acids (BAs) deconjugation and fecal BAs excretion, repaired gut barrier function, activated intestinal Farnesoid X receptor/Fibroblast growth factor 15 (FXR/FGF-15) axis, reduced liver BAs and oxidative stress level, which ultimately mitigated liver damage and fibrosis in both DDC-fed and Mdr2-/- mice. Notably, LAEVs did not ameliorate DDC-induced liver damage or fibrosis in antibiotic-treated mice. Furthermore, LAEVs provided protection against DDC-induced liver injury and fibrosis in fecal microbiota transplantation mice. LAEVs did not ameliorate DDC-induced liver damage or fibrosis in BSH inhibitor (CAPE)-treated mice. LAEVs also failed to improve liver damage and fibrosis in DDC-induced intestinal epithelial cell-specific FXR knockout (Fxr△IE) mice. This study revealed that LAEVs mitigated cholestatic liver fibrosis via regulating gut microbiota-bile acid-ROS axis in mice.
{"title":"Probiotic-derived extracellular vesicles attenuate cholestatic liver damage via gut-liver axis","authors":"Xianjiao Liu , Yanyan Wang , Andrea Abreo Medina , Dandan Liu , Jinyan Liu , Wenxuan Tang , Mengmeng Wang , Xingxiang Chen , Kehe Huang , Min Liu , Chunfeng Wang , Yunhuan Liu","doi":"10.1016/j.phrs.2026.108152","DOIUrl":"10.1016/j.phrs.2026.108152","url":null,"abstract":"<div><div>Gut-liver axis disturbance is the unifying pathogenesis of cholestatic liver diseases. The purpose of this study was to explore the underlying mechanisms of the probiotic <em>Lactobacillus amylovorus</em> (LA) and its secreted extracellular vesicles (EVs) on liver damage and fibrosis in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed and multidrug resistance protein 2 knockout (<em>Mdr2</em><sup><em>-/-</em></sup>) mice. Direct replenishment of LA is sufficient to correct the DDC-fed and <em>Mdr2</em><sup><em>-/-</em></sup>-induced liver damage and fibrosis. Mechanistic studies show that the secretion of EVs is required for the LA-induced liver protective effects. RNA sequencing results demonstrated that the enrichment of differentially expressed genes was associated with glutathione metabolism, microbial metabolism in diverse environments and inflammatory mediator regulation of TRP channels in DDC-fed mice. Our findings revealed that LAEVs reshaped the gut microbiota, which was associated with increased bile acids (BAs) deconjugation and fecal BAs excretion, repaired gut barrier function, activated intestinal Farnesoid X receptor/Fibroblast growth factor 15 (FXR/FGF-15) axis, reduced liver BAs and oxidative stress level, which ultimately mitigated liver damage and fibrosis in both DDC-fed and <em>Mdr2</em><sup><em>-/-</em></sup> mice. Notably, LAEVs did not ameliorate DDC-induced liver damage or fibrosis in antibiotic-treated mice. Furthermore, LAEVs provided protection against DDC-induced liver injury and fibrosis in fecal microbiota transplantation mice. LAEVs did not ameliorate DDC-induced liver damage or fibrosis in BSH inhibitor (CAPE)-treated mice. LAEVs also failed to improve liver damage and fibrosis in DDC-induced intestinal epithelial cell-specific FXR knockout (<em>Fxr</em><sup><em>△IE</em></sup>) mice. This study revealed that LAEVs mitigated cholestatic liver fibrosis via regulating gut microbiota-bile acid-ROS axis in mice.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108152"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147308984","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}
Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.phrs.2026.108112
Chenxi Liu , Yingchun Wang , Yinuo Yang , Miaomiao Tian , Tiantian Liu , Songbo Zhao , Le Wang , Lifen Gao , Yuemin Feng , Jianni Qi , Qiang Zhu
Neuropilin-1 (NRP-1) is a pleiotropic transmembrane receptor critical in embryonic development of neurological and vascular systems. Increasing evidence suggests that NRP-1 has a major role in immunity. However, the role of NRP-1 in regulating the profibrotic function of macrophages during liver fibrosis has not been defined. In this study, we collected human liver samples from 20 patients with fibrosis and 5 controls, finding significantly elevated NRP-1 expression in macrophages from fibrotic livers. Using macrophage-specific NRP-1 deficient mice subjected to CCl₄-induced liver fibrosis, we demonstrated that NRP-1 deficiency effectively attenuated fibrotic progression. Further experiments revealed that NRP-1 enhances profibrotic macrophage polarization and subsequent hepatic stellate cell activation both in vivo and in vitro. Mechanistically, NRP-1 binds to interleukin-13 receptor alpha1 (IL13Rα1) via its extracellular domain, stabilizing the IL13Rα1-IL13 interaction. This activates IL13 signaling, leading to Tyk2 phosphorylation. The IL13Rα1-Tyk2/Stat6 axis then upregulates the transcription factor EHF, which in turn activates NRP-1 expression in macrophages, establishing a positive feedback loop that amplifies profibrotic functions. Our conclusions indicate that NRP-1 promotes liver fibrosis progression, and targeting macrophage NRP-1 is a potential therapeutic strategy against liver fibrosis.
{"title":"Neuropilin-1 acts as a co-receptor of IL-13 to reprogram macrophages in liver fibrosis","authors":"Chenxi Liu , Yingchun Wang , Yinuo Yang , Miaomiao Tian , Tiantian Liu , Songbo Zhao , Le Wang , Lifen Gao , Yuemin Feng , Jianni Qi , Qiang Zhu","doi":"10.1016/j.phrs.2026.108112","DOIUrl":"10.1016/j.phrs.2026.108112","url":null,"abstract":"<div><div>Neuropilin-1 (NRP-1) is a pleiotropic transmembrane receptor critical in embryonic development of neurological and vascular systems. Increasing evidence suggests that NRP-1 has a major role in immunity. However, the role of NRP-1 in regulating the profibrotic function of macrophages during liver fibrosis has not been defined. In this study, we collected human liver samples from 20 patients with fibrosis and 5 controls, finding significantly elevated NRP-1 expression in macrophages from fibrotic livers. Using macrophage-specific NRP-1 deficient mice subjected to CCl₄-induced liver fibrosis, we demonstrated that NRP-1 deficiency effectively attenuated fibrotic progression. Further experiments revealed that NRP-1 enhances profibrotic macrophage polarization and subsequent hepatic stellate cell activation both in vivo and in vitro. Mechanistically, NRP-1 binds to interleukin-13 receptor alpha1 (IL13Rα1) via its extracellular domain, stabilizing the IL13Rα1-IL13 interaction. This activates IL13 signaling, leading to Tyk2 phosphorylation. The IL13Rα1-Tyk2/Stat6 axis then upregulates the transcription factor EHF, which in turn activates NRP-1 expression in macrophages, establishing a positive feedback loop that amplifies profibrotic functions. Our conclusions indicate that NRP-1 promotes liver fibrosis progression, and targeting macrophage NRP-1 is a potential therapeutic strategy against liver fibrosis.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108112"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097424","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}
Pub Date : 2026-03-01Epub Date: 2026-01-31DOI: 10.1016/j.phrs.2026.108123
Dao-Xin Wang , Pin Wang , Zhu-Wei Miao , Shu-Na Wang , Si-Li Zheng , Xue-Lian Wang , Jia-Xin Li , Zhi-Yong Li , Yu Chen , Tian-Guang Zhang , Chao-Yu Miao
We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an in vivo apolipoprotein E-deficient (ApoE-/-) mouse model and an in vitro oxidized low density lipoprotein (ox-LDL)-treated endothelial cell model, METRNL inhibited ox-LDL- or high fat diet-induced atherosclerosis by alleviating endothelial mitochondrial dysfunction and apoptosis which was achieved through a balance between PPARγ co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis and PTEN induced putative kinase protein 1 (PINK1)-Parkin-mediated mitophagy. These findings highlight the pivotal importance of endothelial METRNL against atherosclerosis by comparison with whole-body METRNL. This is the first demonstration of METRNL localization to mitochondria in endothelial cells and its role in maintaining endothelial mitochondrial stability against atherosclerosis. Furthermore, targeting METRNL to stabilize endothelial mitochondrial function represents a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases.
{"title":"Endothelial versus global METRNL reveals importance of endothelial METRNL against atherosclerosis via mitochondrial homeostasis","authors":"Dao-Xin Wang , Pin Wang , Zhu-Wei Miao , Shu-Na Wang , Si-Li Zheng , Xue-Lian Wang , Jia-Xin Li , Zhi-Yong Li , Yu Chen , Tian-Guang Zhang , Chao-Yu Miao","doi":"10.1016/j.phrs.2026.108123","DOIUrl":"10.1016/j.phrs.2026.108123","url":null,"abstract":"<div><div>We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an <em>in vivo apolipoprotein E</em>-deficient (<em>ApoE</em><sup>-/-</sup>) mouse model and an <em>in vitro</em> oxidized low density lipoprotein (ox-LDL)-treated endothelial cell model, METRNL inhibited ox-LDL- or high fat diet-induced atherosclerosis by alleviating endothelial mitochondrial dysfunction and apoptosis which was achieved through a balance between PPARγ co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis and PTEN induced putative kinase protein 1 (PINK1)-Parkin-mediated mitophagy. These findings highlight the pivotal importance of endothelial METRNL against atherosclerosis by comparison with whole-body METRNL. This is the first demonstration of METRNL localization to mitochondria in endothelial cells and its role in maintaining endothelial mitochondrial stability against atherosclerosis. Furthermore, targeting METRNL to stabilize endothelial mitochondrial function represents a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108123"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146106776","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}
Pub Date : 2026-03-01Epub Date: 2026-02-02DOI: 10.1016/j.phrs.2026.108127
Yishan Li , Yang Zhou , Yan Mo , Yixin Li , Peng Wang , Yong Zhao , Li Peng
Histone lactylation is associated with neurological disorders and the state of reactive microglia. However, the impact of elevated lactate levels, generated through glycolysis under hypoxic conditions, on the status and functionality of reactive microglia in the context of ischemic stroke (IS) remains inadequately understood. Immunofluorescence, Western blot and co-immunoprecipitation were performed to identify the histone lactylation modification sites in microglia after IS. CUT&Tag and RNA sequencing data were used to clarify the target genes of H4K5la in microglia after cerebral ischemia. The influence of H4K5la on microglial functions was assessed through Nile Red staining, ELISA, free fatty acid assays, and energy metabolism kits. TTC, behavioral observation, HE and Nissl staining were used to study the impact of exogenous lactate on IS outcomes. Immunofluorescence, Western blot, co-immunoprecipitation, ELISA and qPCR were conducted to explore the upstream regulator of H4K5la and pro-inflammatory gene expression in microglia following IS.H4K5 lactylation level was elevated in microglia and boosted transcription of immunometabolic genes such as HK1, Fads2, and Pla2g4a. This was linked to higher ECAR, lower OCR, impaired FAO, and a reduced ATP/ADP ratio, resulting in more lipid accumulation and increased pro-inflammatory cytokine expression after IS. Exogenous lactate also increased H4K5la levels, indicating that glycolysis-driven lactate enhances histone lactylation. GCN5 was an upstream regulatory factor in modulating microglia histone lactylation and subsequent immune metabolism gene expression after IS. This study reveals the role and mechanism of H4K5la in microglia immunometabolic dysfunction, identifying a new therapeutic target for IS treatment.
{"title":"Histone H4 lysine 5 lactylation: A key regulator of immune metabolism in microglia during ischemic stroke","authors":"Yishan Li , Yang Zhou , Yan Mo , Yixin Li , Peng Wang , Yong Zhao , Li Peng","doi":"10.1016/j.phrs.2026.108127","DOIUrl":"10.1016/j.phrs.2026.108127","url":null,"abstract":"<div><div>Histone lactylation is associated with neurological disorders and the state of reactive microglia. However, the impact of elevated lactate levels, generated through glycolysis under hypoxic conditions, on the status and functionality of reactive microglia in the context of ischemic stroke (IS) remains inadequately understood. Immunofluorescence, Western blot and co-immunoprecipitation were performed to identify the histone lactylation modification sites in microglia after IS. CUT&Tag and RNA sequencing data were used to clarify the target genes of H4K5la in microglia after cerebral ischemia. The influence of H4K5la on microglial functions was assessed through Nile Red staining, ELISA, free fatty acid assays, and energy metabolism kits. TTC, behavioral observation, HE and Nissl staining were used to study the impact of exogenous lactate on IS outcomes. Immunofluorescence, Western blot, co-immunoprecipitation, ELISA and qPCR were conducted to explore the upstream regulator of H4K5la and pro-inflammatory gene expression in microglia following IS.H4K5 lactylation level was elevated in microglia and boosted transcription of immunometabolic genes such as HK1, Fads2, and Pla2g4a. This was linked to higher ECAR, lower OCR, impaired FAO, and a reduced ATP/ADP ratio, resulting in more lipid accumulation and increased pro-inflammatory cytokine expression after IS. Exogenous lactate also increased H4K5la levels, indicating that glycolysis-driven lactate enhances histone lactylation. GCN5 was an upstream regulatory factor in modulating microglia histone lactylation and subsequent immune metabolism gene expression after IS. This study reveals the role and mechanism of H4K5la in microglia immunometabolic dysfunction, identifying a new therapeutic target for IS treatment.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108127"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119456","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}
Metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), diabetes, and their multi-organ complications, are characterized by high prevalence, systemic involvement, and a lack of effective reversal strategies. Their pathological core involves energy metabolism imbalance, chronic inflammation, and multi-tissue injury. In recent years, Sterile Alpha and TIR Motif Containing 1 (SARM1), an NAD⁺ hydrolyzing signaling molecule, has been repositioned from a single executor of axonal degeneration to a cross system metabolic regulatory node. By depleting NAD⁺, disrupting mitochondrial homeostasis, and modulating neuroimmune signaling, SARM1 predominantly exerts pro-injury effects in obesity, NAFLD, cardiac disorders, and peripheral neuropathies. However, in specific cell types, such as hepatic stellate cells, its interaction dependent activity can suppress fibrosis, revealing a striking context dependent duality. Despite these findings, a systematic understanding of SARM1’s cell-type-specific regulation, tissue heterogeneity and long-term intervention safety in metabolic diseases remains limited, thereby constraining its translational potential. This review outlines the structural characteristics and activation mechanisms of SARM1 and, for the first time, discusses its context-dependent roles in metabolic diseases. It also summarizes emerging pharmacological intervention strategies, including small-molecule inhibitors, natural product modulators, and agonists, aiming to provide a theoretical basis for precise interventions in metabolic diseases and to inspire novel therapeutic approaches.
代谢性疾病，包括肥胖、非酒精性脂肪性肝病（NAFLD）、糖尿病及其多器官并发症，具有高患病率、全身性受累和缺乏有效逆转策略的特点。其病理核心包括能量代谢失衡、慢性炎症和多组织损伤。近年来，NAD +水解信号分子SARM1 （Sterile Alpha and TIR Motif Containing 1）已经从轴突变性的单一执行者重新定位为跨系统代谢调节节点。通过消耗NAD +、破坏线粒体稳态和调节神经免疫信号，SARM1主要在肥胖、NAFLD、心脏疾病和周围神经病变中发挥促损伤作用。然而，在特定的细胞类型中，如肝星状细胞，其相互作用依赖性活性可以抑制纤维化，揭示出一种显著的环境依赖性双重性。尽管有这些发现，但对SARM1在代谢性疾病中的细胞类型特异性调控、组织异质性和长期干预安全性的系统理解仍然有限，从而限制了其翻译潜力。本文概述了SARM1的结构特征和激活机制，并首次讨论了其在代谢性疾病中的环境依赖性作用。它还总结了新兴的药物干预策略，包括小分子抑制剂、天然产物调节剂和激动剂，旨在为代谢性疾病的精确干预提供理论基础，并激发新的治疗方法。
{"title":"Targeting the SARM1-NAD⁺ axis: A review of new strategy for reversing the imbalance of energy and mitochondrial homeostasis in metabolic diseases","authors":"Ao Xiong , Wen Lv , Xiaoqi Shao , Yanjie Lv , Yue Zhang","doi":"10.1016/j.phrs.2026.108128","DOIUrl":"10.1016/j.phrs.2026.108128","url":null,"abstract":"<div><div>Metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), diabetes, and their multi-organ complications, are characterized by high prevalence, systemic involvement, and a lack of effective reversal strategies. Their pathological core involves energy metabolism imbalance, chronic inflammation, and multi-tissue injury. In recent years, Sterile Alpha and TIR Motif Containing 1 (SARM1), an NAD⁺ hydrolyzing signaling molecule, has been repositioned from a single executor of axonal degeneration to a cross system metabolic regulatory node. By depleting NAD⁺, disrupting mitochondrial homeostasis, and modulating neuroimmune signaling, SARM1 predominantly exerts pro-injury effects in obesity, NAFLD, cardiac disorders, and peripheral neuropathies. However, in specific cell types, such as hepatic stellate cells, its interaction dependent activity can suppress fibrosis, revealing a striking context dependent duality. Despite these findings, a systematic understanding of SARM1’s cell-type-specific regulation, tissue heterogeneity and long-term intervention safety in metabolic diseases remains limited, thereby constraining its translational potential. This review outlines the structural characteristics and activation mechanisms of SARM1 and, for the first time, discusses its context-dependent roles in metabolic diseases. It also summarizes emerging pharmacological intervention strategies, including small-molecule inhibitors, natural product modulators, and agonists, aiming to provide a theoretical basis for precise interventions in metabolic diseases and to inspire novel therapeutic approaches.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108128"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132705","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}
Pub Date : 2026-03-01Epub Date: 2026-01-23DOI: 10.1016/j.phrs.2026.108111
Lili Fan , Xiaowei Mo , Ranran Dai , Jingman Tang , Chunmiao Wan , Shaoyi Fang , Xuan Zhou , Qingyu Ma , Xuxu Zhuang , Yueyue Chen , Xiaojuan Li , Jiaxu Chen
Xiaoyaosan (XYS) is a classical traditional prescription with well-documented antidepressant effects. However, the active components and molecular mechanisms to alleviate depression remain unclear. In this study, using chronic social defeat stress (CSDS) and lipopolysaccharide (LPS)-induced depression models, we found that XYS and its key ingredient isoliquiritigenin (ILG) not only significantly improved depressive-like behaviors in mice but also exerted dual regulatory effects at the cellular level, promoting hippocampal neural stem cell proliferation and differentiation, while inhibiting microglia-mediated neuroinflammation. Using Hi-C technology, we discovered that XYS and ILG reversed the abnormal chromatin 3D structure in hippocampal microglia of depression models. Integrated analyses of transcriptomics, molecular docking, and 3D genomics identified the transcription factor p65 as a target of XYS and ILG. Co-culture experiments with microglia and neural stem cells further confirmed that overexpression of p65 promotes inflammation and inhibits neuronal growth. In depressed mice, NF-κB p65 expression was elevated and further formed phase separated condensates, which was effectively suppressed by XYS and ILG. This study reveals how XYS and its active component ILG function mechanistically to exert therapeutic effects on depression, including restoring chromatin 3D structure, and normalizing pathological phase separation of NF-κB p65, and reversing depressive phenotypes. Collectively, these findings provide a solid experimental foundation for the development of natural antidepressants.
{"title":"Xiaoyaosan and isoliquiritigenin remodel depression-associated chromatin 3D structure and phase separation of NF-κB p65","authors":"Lili Fan , Xiaowei Mo , Ranran Dai , Jingman Tang , Chunmiao Wan , Shaoyi Fang , Xuan Zhou , Qingyu Ma , Xuxu Zhuang , Yueyue Chen , Xiaojuan Li , Jiaxu Chen","doi":"10.1016/j.phrs.2026.108111","DOIUrl":"10.1016/j.phrs.2026.108111","url":null,"abstract":"<div><div>Xiaoyaosan (XYS) is a classical traditional prescription with well-documented antidepressant effects. However, the active components and molecular mechanisms to alleviate depression remain unclear. In this study, using chronic social defeat stress (CSDS) and lipopolysaccharide (LPS)-induced depression models, we found that XYS and its key ingredient isoliquiritigenin (ILG) not only significantly improved depressive-like behaviors in mice but also exerted dual regulatory effects at the cellular level, promoting hippocampal neural stem cell proliferation and differentiation, while inhibiting microglia-mediated neuroinflammation. Using Hi-C technology, we discovered that XYS and ILG reversed the abnormal chromatin 3D structure in hippocampal microglia of depression models. Integrated analyses of transcriptomics, molecular docking, and 3D genomics identified the transcription factor p65 as a target of XYS and ILG. Co-culture experiments with microglia and neural stem cells further confirmed that overexpression of p65 promotes inflammation and inhibits neuronal growth. In depressed mice, NF-κB p65 expression was elevated and further formed phase separated condensates, which was effectively suppressed by XYS and ILG. This study reveals how XYS and its active component ILG function mechanistically to exert therapeutic effects on depression, including restoring chromatin 3D structure, and normalizing pathological phase separation of NF-κB p65, and reversing depressive phenotypes. Collectively, these findings provide a solid experimental foundation for the development of natural antidepressants.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"225 ","pages":"Article 108111"},"PeriodicalIF":10.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045964","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}
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