Pub Date : 2026-01-01DOI: 10.1016/j.phrs.2025.108071
Emanuela Bottani , Francesca Ciarpella , Benedetta Lucidi , Giulia Pedrotti , Chiara Santanatoglia , Eros Rossi , Enrica Cappellozza , Elisa De Tomi , Sissi Dolci , Giovanni Malerba , Giorgio Malpeli , Ilaria Decimo
Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas Ppargc1a gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment via activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.
{"title":"Targeting PGC-1α axis rescues aberrant development from thyroid hormone defect in brain organoids","authors":"Emanuela Bottani , Francesca Ciarpella , Benedetta Lucidi , Giulia Pedrotti , Chiara Santanatoglia , Eros Rossi , Enrica Cappellozza , Elisa De Tomi , Sissi Dolci , Giovanni Malerba , Giorgio Malpeli , Ilaria Decimo","doi":"10.1016/j.phrs.2025.108071","DOIUrl":"10.1016/j.phrs.2025.108071","url":null,"abstract":"<div><div>Thyroid hormone (T3) deficiency during central nervous system development leads to severe and often incurable human pathologies, including intellectual disability and motor dysfunction. Using murine dorsal forebrain organoids, we showed that T3 is required to activate mitochondrial β-oxidation and OXPHOS biogenesis to sustain neuronal development, while its absence caused profound neurodevelopmental defects such as defective maturation, astrogliosis, and reduced spontaneous activity. Mechanistically, we identified the transcriptional coactivator PGC-1α as a central mediator of the T3 effect. Pharmacological inhibition of β-oxidation in T3-supplemented organoids recapitulated the T3-deficient phenotype, whereas <em>Ppargc1a</em> gene augmentation rescued neuronal development under T3-deprived conditions. Most importantly, pharmacological stimulation of the PGC-1α axis with Nicotinamide Riboside or Bezafibrate rescues mitochondrial bioenergetics and neuronal development, effectively correcting aberrant brain organoid maturation despite T3 deficiency. These findings reveal for the first time the role of T3 in supporting neurodevelopment <em>via</em> activation of mitochondrial β-oxidation and OXPHOS biogenesis, and identify the PGC-1α axis as a promising therapeutic avenue for otherwise intractable disorders linked to thyroid hormone deficiency.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108071"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794250","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108072
Sebastiano A. Torrisi , Maria Rosaria Tropea , Silvia Rizzo , Mattia Giovenzana , Chiara Magri , Alessandro Barbon , Jessica Mingardi , Clizia Chinello , Lisa Pagani , Isabella Piga , Loredana Leggio , Nunzio Iraci , Walter Gulisano , Filippo Drago , Daniela Puzzo , Laura Musazzi , Gian Marco Leggio
Although post-traumatic stress disorder (PTSD) occurs more in women than in men, how sex influences trauma susceptibility remains largely unknown. We developed the arousal-based individual screening (AIS) model, which identifies mice as susceptible/resilient to PTSD-like phenotypes, based on changes in startle reactivity induced by 24-hour-restraint. To test the hypothesis that sex drives trauma susceptibility/resilience, we applied a multidisciplinary approach involving electrophysiological, structural, and synaptoproteomic analyses of the hippocampus in susceptible and resilient mice of both sexes. Female mice were more susceptible to the trauma than male mice and exhibited long-lasting PTSD-like phenotypes. Long-term potentiation (LTP) was impaired in hippocampal slices of both male and female susceptible mice, whereas short-term presynaptic forms of plasticity and vesicle recycling remained unchanged. Increased apical dendritic length and augmented basal dendritic spine density of pyramidal neurons were found in CA1 of male susceptible mice, while decreased dendritic length of granule neurons was uncovered in the dentate gyrus of female resilient mice. Although minor synaptoproteomic changes were observed, bioinformatic analysis suggested sex- and susceptibility/resilience-dependent profiles. Notably, several pathways involving RHO Family GTPases were found to be upregulated exclusively in susceptible male mice. Accordingly, the Rac1/Rac3 GTPases inhibitor EHop-016 rescued the hippocampal LTP impairment in susceptible male mice but not in susceptible female mice. Our findings suggest that the AIS model mirrors sex differences in PTSD susceptibility/resilience highlighting associated functional, molecular and structural alterations. This model may represent a critical first step for studying sex-dependent pathophysiological mechanisms subserving PTSD susceptibility and for sex-tailored drug development.
{"title":"Functional, synaptoproteomic and structural adaptations underlying sex-dependent traumatic stress susceptibility/resilience in the hippocampus","authors":"Sebastiano A. Torrisi , Maria Rosaria Tropea , Silvia Rizzo , Mattia Giovenzana , Chiara Magri , Alessandro Barbon , Jessica Mingardi , Clizia Chinello , Lisa Pagani , Isabella Piga , Loredana Leggio , Nunzio Iraci , Walter Gulisano , Filippo Drago , Daniela Puzzo , Laura Musazzi , Gian Marco Leggio","doi":"10.1016/j.phrs.2025.108072","DOIUrl":"10.1016/j.phrs.2025.108072","url":null,"abstract":"<div><div>Although post-traumatic stress disorder (PTSD) occurs more in women than in men, how sex influences trauma susceptibility remains largely unknown. We developed the arousal-based individual screening (AIS) model, which identifies mice as susceptible/resilient to PTSD-like phenotypes, based on changes in startle reactivity induced by 24-hour-restraint. To test the hypothesis that sex drives trauma susceptibility/resilience, we applied a multidisciplinary approach involving electrophysiological, structural, and synaptoproteomic analyses of the hippocampus in susceptible and resilient mice of both sexes. Female mice were more susceptible to the trauma than male mice and exhibited long-lasting PTSD-like phenotypes. Long-term potentiation (LTP) was impaired in hippocampal slices of both male and female susceptible mice, whereas short-term presynaptic forms of plasticity and vesicle recycling remained unchanged. Increased apical dendritic length and augmented basal dendritic spine density of pyramidal neurons were found in CA1 of male susceptible mice, while decreased dendritic length of granule neurons was uncovered in the dentate gyrus of female resilient mice. Although minor synaptoproteomic changes were observed, bioinformatic analysis suggested sex- and susceptibility/resilience-dependent profiles. Notably, several pathways involving RHO Family GTPases were found to be upregulated exclusively in susceptible male mice. Accordingly, the Rac1/Rac3 GTPases inhibitor EHop-016 rescued the hippocampal LTP impairment in susceptible male mice but not in susceptible female mice. Our findings suggest that the AIS model mirrors sex differences in PTSD susceptibility/resilience highlighting associated functional, molecular and structural alterations. This model may represent a critical first step for studying sex-dependent pathophysiological mechanisms subserving PTSD susceptibility and for sex-tailored drug development.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108072"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843846","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 : 2026-01-01DOI: 10.1016/j.phrs.2025.108078
Nemanja Garai , Sanja Madic , Vukan Ivanovic , Aleksa Palibrk , Jovan Pesovic , Milos Brkusanin , Ivana Basta , Stojan Peric , Dusanka Savic-Pavicevic
Insufficient effectiveness and adverse effects of immunosuppressive therapy, seen in around 20 % of acetylcholine receptor (AChR) positive myasthenia gravis (MG) patients, highlight the need for new biomarkers. MicroRNAs (miRNAs), small regulatory non-coding RNAs with tissue-specific expression, have emerged as potential biomarkers due to their abundance and accessibility in body fluids. Several miRNAs involved in immune system and drug metabolism have been associated with improvement of neuromuscular status or response to immunosuppressive therapy in AChR-positive MG patients in cross-sectional studies. Here, we explored miRNAs as plasma biomarkers for immunosuppressive therapy response in a prospective longitudinal study of newly diagnosed, drug-naïve patients. Clinical examination and plasma sampling were performed at three time points: baseline (pre-treatment), 6-month, and 12-month follow-ups. MiRNA levels were quantified by qPCR. Three out of eight analyzed miRNAs (miR-150–5p, miR-27a–3p, and miR-21–5p) showed treatment-related changes. Among them, miR-150–5p level was negatively correlated with patient functionality (MG Activities of Daily Living score – MG-ADL; p = 0.007, ρs=−0.433), muscle strength and weakness (Quantitative MG score – QMG; p = 0.002, ρs=−0.355) and overall symptoms (MG Composite score – MGC; p = 7.814e-5, ρs=−0.457). Pre-treatment miR-150–5p levels showed excellent prognostic ability to discriminate responders from not-responders based on achieved minimal clinical expression (AUC=0.85, p = 0.0076) and MG-ADL (AUC=0.86, p = 0.016) at 12-month follow-up. Predictive performance was also acceptable based on QMG and MGC (AUC=0.74, p = 0.001 and AUC=0.73, p = 0.0002, respectively). Our findings imply plasma miR-150–5p as a potential biomarker for predicting immunosuppressive therapy response in AChR-positive MG, suggesting its further investigation for disease monitoring and a personalized medicine approach.
{"title":"Plasma miR-150–5p as a biomarker for immunosuppressive therapy response in acetylcholine receptor positive myasthenia gravis: a long-term prospective longitudinal study","authors":"Nemanja Garai , Sanja Madic , Vukan Ivanovic , Aleksa Palibrk , Jovan Pesovic , Milos Brkusanin , Ivana Basta , Stojan Peric , Dusanka Savic-Pavicevic","doi":"10.1016/j.phrs.2025.108078","DOIUrl":"10.1016/j.phrs.2025.108078","url":null,"abstract":"<div><div>Insufficient effectiveness and adverse effects of immunosuppressive therapy, seen in around 20 % of acetylcholine receptor (AChR) positive myasthenia gravis (MG) patients, highlight the need for new biomarkers. MicroRNAs (miRNAs), small regulatory non-coding RNAs with tissue-specific expression, have emerged as potential biomarkers due to their abundance and accessibility in body fluids. Several miRNAs involved in immune system and drug metabolism have been associated with improvement of neuromuscular status or response to immunosuppressive therapy in AChR-positive MG patients in cross-sectional studies. Here, we explored miRNAs as plasma biomarkers for immunosuppressive therapy response in a prospective longitudinal study of newly diagnosed, drug-naïve patients. Clinical examination and plasma sampling were performed at three time points: baseline (pre-treatment), 6-month, and 12-month follow-ups. MiRNA levels were quantified by qPCR. Three out of eight analyzed miRNAs (miR-150–5p, miR-27a–3p, and miR-21–5p) showed treatment-related changes. Among them, miR-150–5p level was negatively correlated with patient functionality (MG Activities of Daily Living score – MG-ADL; p = 0.007, ρ<sub>s</sub>=−0.433), muscle strength and weakness (Quantitative MG score – QMG; p = 0.002, ρ<sub>s</sub>=−0.355) and overall symptoms (MG Composite score – MGC; p = 7.814e-5, ρ<sub>s</sub>=−0.457). Pre-treatment miR-150–5p levels showed excellent prognostic ability to discriminate responders from not-responders based on achieved minimal clinical expression (AUC=0.85, p = 0.0076) and MG-ADL (AUC=0.86, p = 0.016) at 12-month follow-up. Predictive performance was also acceptable based on QMG and MGC (AUC=0.74, p = 0.001 and AUC=0.73, p = 0.0002, respectively). Our findings imply plasma miR-150–5p as a potential biomarker for predicting immunosuppressive therapy response in AChR-positive MG, suggesting its further investigation for disease monitoring and a personalized medicine approach.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108078"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846390","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":"Corrigendum to “Tagitinin F has anti-inflammatory, anti-nociceptive and anti-matrix metalloproteinase properties: An in silico, in vitro and in vivo study” [Pharmacol. Res. 164 (2021) 105303]","authors":"Laíla Pereira Silva , Eliziária Cardoso Santos , Bruno Arantes Borges , Marcia Paranho Veloso , Daniela Aparecida Chagas-Paula , Reggiani Vilela Gonçalves , Rômulo Dias Novaes","doi":"10.1016/j.phrs.2025.108070","DOIUrl":"10.1016/j.phrs.2025.108070","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108070"},"PeriodicalIF":10.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782399","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 : 2025-12-31DOI: 10.1016/j.phrs.2025.108081
Yan Ye , Qian Zeng , Zuli Ou , Xiaoqian Ju , Qingyu Liao , Canling Li , Dian Zhang , Yu Wei , Xiang Zhang , Kejia Wu , Tingmei Chen
Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.
{"title":"Mitochondrial pyruvate dehydrogenase kinase 1 drives bevacizumab resistance and malignant phenotype of TNBC by enhancing mitophagy","authors":"Yan Ye , Qian Zeng , Zuli Ou , Xiaoqian Ju , Qingyu Liao , Canling Li , Dian Zhang , Yu Wei , Xiang Zhang , Kejia Wu , Tingmei Chen","doi":"10.1016/j.phrs.2025.108081","DOIUrl":"10.1016/j.phrs.2025.108081","url":null,"abstract":"<div><div>Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108081"},"PeriodicalIF":10.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892954","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 : 2025-12-29DOI: 10.1016/j.phrs.2025.108080
Martina Colognesi , Daniela Gabbia , Anna Signor , Miles Sarill , Lucia Centofanti , Andrea Rinaldi , Luciano Cascione , Sara Nunziata , Marco Banzato , Andrea Mattarei , Giovanna Finzi , Sonia Sonda , Diana Pendin , Ilaria Zanotto , Stefano Comai , Gianfranco Pasut , Abdullah Alajati , Miriam Saponaro , Loredana Bucciarelli , Maria Elena Lunati , Sara De Martin
The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.
{"title":"Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms","authors":"Martina Colognesi , Daniela Gabbia , Anna Signor , Miles Sarill , Lucia Centofanti , Andrea Rinaldi , Luciano Cascione , Sara Nunziata , Marco Banzato , Andrea Mattarei , Giovanna Finzi , Sonia Sonda , Diana Pendin , Ilaria Zanotto , Stefano Comai , Gianfranco Pasut , Abdullah Alajati , Miriam Saponaro , Loredana Bucciarelli , Maria Elena Lunati , Sara De Martin","doi":"10.1016/j.phrs.2025.108080","DOIUrl":"10.1016/j.phrs.2025.108080","url":null,"abstract":"<div><div>The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108080"},"PeriodicalIF":10.5,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878794","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 : 2025-12-23DOI: 10.1016/j.phrs.2025.108079
Song-Song Shi , Yu-Dan Du , Si-Yi Chen , Wen Zhang , Guo-Wu Rao , Quan Zheng
Phosphoglycerate dehydrogenase (PHGDH) has emerged as a promising therapeutic target due to its critical roles in the pathogenesis of cancer and neurological disorders. Targeting PHGDH holds significant theoretical and translational potential for cancer therapy and the amelioration of cognitive impairments. However, currently available PHGDH inhibitors are limited in number and primarily function through inhibition of the enzyme's catalytic activity. This review systematically summarizes PHGDH modulators identified from traditional Chinese medicine, including both inhibitors and activators, and presents a detailed analysis of their structure–activity relationships (SAR) and mechanisms of action. It also comprehensively outlines the signaling pathways that regulate PHGDH degradation through the ubiquitin–proteasome system and autophagy–lysosome pathway. Importantly, it also discusses emerging targeted protein degradation (TPD) technologies, including PROTACs, LYTACs, AUTACs, and ATTECs. The development of these frontier technologies has opened new pathways for mitigating the limitations of existing inhibitors.
{"title":"PHGDH as a therapeutic node: Natural modulators from TCM, degradation pathways, and emerging TPD strategies","authors":"Song-Song Shi , Yu-Dan Du , Si-Yi Chen , Wen Zhang , Guo-Wu Rao , Quan Zheng","doi":"10.1016/j.phrs.2025.108079","DOIUrl":"10.1016/j.phrs.2025.108079","url":null,"abstract":"<div><div>Phosphoglycerate dehydrogenase (PHGDH) has emerged as a promising therapeutic target due to its critical roles in the pathogenesis of cancer and neurological disorders. Targeting PHGDH holds significant theoretical and translational potential for cancer therapy and the amelioration of cognitive impairments. However, currently available PHGDH inhibitors are limited in number and primarily function through inhibition of the enzyme's catalytic activity. This review systematically summarizes PHGDH modulators identified from traditional Chinese medicine, including both inhibitors and activators, and presents a detailed analysis of their structure–activity relationships (SAR) and mechanisms of action. It also comprehensively outlines the signaling pathways that regulate PHGDH degradation through the ubiquitin–proteasome system and autophagy–lysosome pathway. Importantly, it also discusses emerging targeted protein degradation (TPD) technologies, including PROTACs, LYTACs, AUTACs, and ATTECs. The development of these frontier technologies has opened new pathways for mitigating the limitations of existing inhibitors.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108079"},"PeriodicalIF":10.5,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834543","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 : 2025-12-18DOI: 10.1016/j.phrs.2025.108074
Hao-wen Lin , Shi-pian Li , Jia-xin Wen , Jia-xuan Zhang , Bi-meng Zhang , Yong-jun Wang , Xue-jun Cui , Min Yao
Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from Panax notoginseng (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer’s disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.
{"title":"Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects","authors":"Hao-wen Lin , Shi-pian Li , Jia-xin Wen , Jia-xuan Zhang , Bi-meng Zhang , Yong-jun Wang , Xue-jun Cui , Min Yao","doi":"10.1016/j.phrs.2025.108074","DOIUrl":"10.1016/j.phrs.2025.108074","url":null,"abstract":"<div><div>Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from <em>Panax notoginseng</em> (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer’s disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"224 ","pages":"Article 108074"},"PeriodicalIF":10.5,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800202","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}
Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder pathologically defined by valvular sclerosis, fibrosis, and ectopic mineralization, which constitutes a substantial and growing public health burden. Currently, surgical intervention represents the sole effective treatment, underscoring a critical unmet need for novel pharmacological strategies that can halt disease progression or provide early therapeutic intervention. Extensive research has established that the pathogenesis of CAVD is driven by a complex interplay of multiple mechanisms including inflammatory responses, oxidative stress, and metabolic dysregulation which are intricately modulated by epigenetic regulation, post-transcriptional modifications, and protein post-translational modifications. In recent years, the field of epigenetics has garnered considerable attention, particularly for its pivotal role in the pathogenesis of oncological and cardiovascular diseases and the subsequent development of targeted therapeutic strategies. Consequently, numerous investigations have been dedicated to elucidating the involvement of epigenetic mechanisms in CAVD, encompassing DNA methylation, histone modifications (including methylation and acetylation), and RNA methylation, with a pronounced emphasis on the regulatory functions of non-coding RNAs. This review synthesizes recent advances in our understanding of epigenetic mechanisms underlying CAVD, with a specific focus on the role of RNA N6-methyladenosine (m6A) methylation, and highlights the pivotal significance of epigenetic modulation in critical biological processes and CAVD pathogenesis. Collectively, these findings offer valuable mechanistic insights and may illuminate novel paths toward the clinical translation of epigenetically targeted therapies for CAVD.
{"title":"Epigenetic Regulation in calcific aortic valve disease: Mechanisms and therapeutic potential","authors":"Hanshen Luo, Yuehang Yang, Chiyang Xie, Chuli Shi, Siyuan Liu, Jiawei Shi","doi":"10.1016/j.phrs.2025.108073","DOIUrl":"10.1016/j.phrs.2025.108073","url":null,"abstract":"<div><div>Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder pathologically defined by valvular sclerosis, fibrosis, and ectopic mineralization, which constitutes a substantial and growing public health burden. Currently, surgical intervention represents the sole effective treatment, underscoring a critical unmet need for novel pharmacological strategies that can halt disease progression or provide early therapeutic intervention. Extensive research has established that the pathogenesis of CAVD is driven by a complex interplay of multiple mechanisms including inflammatory responses, oxidative stress, and metabolic dysregulation which are intricately modulated by epigenetic regulation, post-transcriptional modifications, and protein post-translational modifications. In recent years, the field of epigenetics has garnered considerable attention, particularly for its pivotal role in the pathogenesis of oncological and cardiovascular diseases and the subsequent development of targeted therapeutic strategies. Consequently, numerous investigations have been dedicated to elucidating the involvement of epigenetic mechanisms in CAVD, encompassing DNA methylation, histone modifications (including methylation and acetylation), and RNA methylation, with a pronounced emphasis on the regulatory functions of non-coding RNAs. This review synthesizes recent advances in our understanding of epigenetic mechanisms underlying CAVD, with a specific focus on the role of RNA N6-methyladenosine (m6A) methylation, and highlights the pivotal significance of epigenetic modulation in critical biological processes and CAVD pathogenesis. Collectively, these findings offer valuable mechanistic insights and may illuminate novel paths toward the clinical translation of epigenetically targeted therapies for CAVD.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"223 ","pages":"Article 108073"},"PeriodicalIF":10.5,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788859","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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