Pub Date : 2025-12-01DOI: 10.1016/j.phrs.2025.108051
Sophie Post , Lena Rueschpler , Sebastian Schloer
Emerging viruses exploit the endolysosomal system to enter host cells, subvert immune defenses, and promote their replication, underscoring the need for a deeper understanding of this compartment at the host-pathogen interface. This review synthesizes current advances that position endolysosomes as central gatekeepers of cellular homeostasis and viral control. We illustrate how emerging viruses co-opt endolysosomal trafficking pathways for entry, uncoating, and propagation; how they manipulate autophagy and key signaling nodes such as mTORC1, TFEB, and the ESCRT machinery; and how they strategically disrupt innate immune signaling orchestrated from endolysosomal platforms. We further highlight recent discoveries revealing viral interference with endosomal pattern-recognition receptors, antigen presentation circuits, and downstream inflammatory signaling. Finally, we critically assess emerging therapeutic strategies that target endolysosomal functions to restrict viral infection. Together, these insights provide an integrated framework for understanding how endolysosomes shape host antiviral responses and how their dysregulation is exploited by diverse, rapidly evolving viral pathogens. Nevertheless, the clinical translation of endolysosome-targeted antiviral strategies remains constrained by pathway complexity, potential off-target effects, and the absence of reliable biomarkers to guide therapeutic precision, underscoring key limitations and opportunities for future investigation.
{"title":"Endolysosomes as a sorting hub for emerging viruses: Gatekeepers of cellular defense, viral fate and promising therapeutic target","authors":"Sophie Post , Lena Rueschpler , Sebastian Schloer","doi":"10.1016/j.phrs.2025.108051","DOIUrl":"10.1016/j.phrs.2025.108051","url":null,"abstract":"<div><div>Emerging viruses exploit the endolysosomal system to enter host cells, subvert immune defenses, and promote their replication, underscoring the need for a deeper understanding of this compartment at the host-pathogen interface. This review synthesizes current advances that position endolysosomes as central gatekeepers of cellular homeostasis and viral control. We illustrate how emerging viruses co-opt endolysosomal trafficking pathways for entry, uncoating, and propagation; how they manipulate autophagy and key signaling nodes such as mTORC1, TFEB, and the ESCRT machinery; and how they strategically disrupt innate immune signaling orchestrated from endolysosomal platforms. We further highlight recent discoveries revealing viral interference with endosomal pattern-recognition receptors, antigen presentation circuits, and downstream inflammatory signaling. Finally, we critically assess emerging therapeutic strategies that target endolysosomal functions to restrict viral infection. Together, these insights provide an integrated framework for understanding how endolysosomes shape host antiviral responses and how their dysregulation is exploited by diverse, rapidly evolving viral pathogens. Nevertheless, the clinical translation of endolysosome-targeted antiviral strategies remains constrained by pathway complexity, potential off-target effects, and the absence of reliable biomarkers to guide therapeutic precision, underscoring key limitations and opportunities for future investigation.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108051"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669161","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 : 2025-12-01DOI: 10.1016/j.phrs.2025.108058
Robert Roskoski Jr.
The human PARP enzyme family contains 17 members that are divided into five subfamilies, the chief one of which includes the DNA-dependent enzymes (PARP1/2/3). These enzymes participate, inter alia, in DNA repair, transcription, chromatin remodeling, and cells cycle progression. PARP 1/2 catalyze both the mono-ADP ribosylation (MARylation) and poly-ADP ribosylation (PARylation) of its various substrates including itself. PARP1/2 catalyze the formation of large (200 units) linear and branched ADP-ribosyl polymer chains. When the PARP enzyme binds to DNA containing various lesions, it is activated. ADP ribosylated PARPs mark the sites of DNA damage and attract repair proteins. Back-of-the-envelope calculations suggest that the number of single-strand breaks and base loss or modification ranges from 10,000 to 100,000 per cell per day. To function properly, at least in proliferating and germline cells, the DNA lesions must be repaired. Otherwise, cell death may ensue or deleterious mutations that can cause cancer or cell senescence can occur. The FDA has approved four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) for the treatment of ovarian, breast, prostate, and pancreatic cancer. These agents are approved for cancers with homologous-recombination repair deficiencies including BRCA1/2 mutations. These inhibitors are approved agents used for neoadjuvant, adjuvant, and maintenance therapies. The Chinese NMPA has approved three PARP antagonists (fuzuloparib, pamiparib, senaparib) for the treatment of ovarian cancer. All seven of these drugs are orally bioavailable and fall within the criteria of Lipinski’s rule of five. Drug resistance develops in most PARP-inhibitor-treated cancer patients within one or two years.
{"title":"Poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of cancer","authors":"Robert Roskoski Jr.","doi":"10.1016/j.phrs.2025.108058","DOIUrl":"10.1016/j.phrs.2025.108058","url":null,"abstract":"<div><div>The human PARP enzyme family contains 17 members that are divided into five subfamilies, the chief one of which includes the DNA-dependent enzymes (PARP1/2/3). These enzymes participate, <em>inter alia</em>, in DNA repair, transcription, chromatin remodeling, and cells cycle progression. PARP 1/2 catalyze both the mono-ADP ribosylation (MARylation) and poly-ADP ribosylation (PARylation) of its various substrates including itself. PARP1/2 catalyze the formation of large (200 units) linear and branched ADP-ribosyl polymer chains. When the PARP enzyme binds to DNA containing various lesions, it is activated. ADP ribosylated PARPs mark the sites of DNA damage and attract repair proteins. Back-of-the-envelope calculations suggest that the number of single-strand breaks and base loss or modification ranges from 10,000 to 100,000 per cell per day. To function properly, at least in proliferating and germline cells, the DNA lesions must be repaired. Otherwise, cell death may ensue or deleterious mutations that can cause cancer or cell senescence can occur. The FDA has approved four PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib) for the treatment of ovarian, breast, prostate, and pancreatic cancer. These agents are approved for cancers with homologous-recombination repair deficiencies including <em>BRCA1/2</em> mutations. These inhibitors are approved agents used for neoadjuvant, adjuvant, and maintenance therapies. The Chinese NMPA has approved three PARP antagonists (fuzuloparib, pamiparib, senaparib) for the treatment of ovarian cancer. All seven of these drugs are orally bioavailable and fall within the criteria of Lipinski’s rule of five. Drug resistance develops in most PARP-inhibitor-treated cancer patients within one or two years.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108058"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687836","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 : 2025-12-01DOI: 10.1016/j.phrs.2025.108014
Guido Grassi
{"title":"The saga of the guidelines on hypertension: Focus on the 2025 ACC/AHA document","authors":"Guido Grassi","doi":"10.1016/j.phrs.2025.108014","DOIUrl":"10.1016/j.phrs.2025.108014","url":null,"abstract":"","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108014"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409001","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 : 2025-12-01DOI: 10.1016/j.phrs.2025.108061
Bingchen Pan , Tan Li , Na Deng , Xin Zhang , Yangjie Peng , Yanke Li , Jingjing Jing , Liping Sun
Solute carrier (SLC) transporters exert a crucial effect on metalloptosis in tumors via governing the translocation of ions and amino acids across cellular and organelle membranes. Disruptions in metal ion homeostasis mediated by SLC transporters, along with the subsequent induction of metalloptosis, are pivotal factors in tumor initiation and progression. However, the precise biological roles and clinical implications of SLC transporters in cancer remain incompletely interpreted. This review systematically summarizes the structural and functional features of SLC transporters in mediating metalloptosis and underscores their significant roles in cancer biology. We further delineate the regulatory mechanisms of SLC transporters in metal ion flux and amino acid metabolism, emphasizing their dynamic interplay in modulating metalloptosis during tumorigenesis. Furthermore, we provide a detailed overview of the complex crosstalk among SLC transporters, metal ions, and metalloptosis pathways, and highlight the role of SLC transporters in cancer, paving novel avenues for innovative anticancer strategies.
{"title":"SLC transporters as metalloptotic gatekeepers in tumorigenesis: From molecular mechanisms to clinical potential","authors":"Bingchen Pan , Tan Li , Na Deng , Xin Zhang , Yangjie Peng , Yanke Li , Jingjing Jing , Liping Sun","doi":"10.1016/j.phrs.2025.108061","DOIUrl":"10.1016/j.phrs.2025.108061","url":null,"abstract":"<div><div>Solute carrier (SLC) transporters exert a crucial effect on metalloptosis in tumors via governing the translocation of ions and amino acids across cellular and organelle membranes. Disruptions in metal ion homeostasis mediated by SLC transporters, along with the subsequent induction of metalloptosis, are pivotal factors in tumor initiation and progression. However, the precise biological roles and clinical implications of SLC transporters in cancer remain incompletely interpreted. This review systematically summarizes the structural and functional features of SLC transporters in mediating metalloptosis and underscores their significant roles in cancer biology. We further delineate the regulatory mechanisms of SLC transporters in metal ion flux and amino acid metabolism, emphasizing their dynamic interplay in modulating metalloptosis during tumorigenesis. Furthermore, we provide a detailed overview of the complex crosstalk among SLC transporters, metal ions, and metalloptosis pathways, and highlight the role of SLC transporters in cancer, paving novel avenues for innovative anticancer strategies.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108061"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145691007","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 : 2025-12-01DOI: 10.1016/j.phrs.2025.108046
Bing Shu , Xisha Chen , Zhonghao Liu , Huifang Tang , Bo Yang , Chengxiao Fu
SGLT2 inhibitors, initially developed for type 2 diabetes management, have primarily demonstrated pleiotropic benefits in cardiovascular, renal, pulmonary, digestive and endocrine/metabolic, et al. Emerging evidence highlights their immunomodulatory effects on macrophages, key players in disease pathogenesis. This review summarizes the mechanisms by which dapagliflozin, empagliflozin, and canagliflozin regulate macrophage polarization, metabolic reprogramming, and inflammatory responses. These drugs suppress pro-inflammatory M1 macrophage activation, promote anti-inflammatory M2 phenotypes, and reduce the release of cytokines (e.g., IL-1β, IL-6,TNF-α) through pathways such as NF-κB, AMPK/mTOR, and JAK/STAT. In cardiovascular diseases, they attenuate atherosclerosis (AS) and myocardial fibrosis by limiting macrophage infiltration and foam cell formation. Renal protection is mediated via reduced macrophage-driven inflammation and fibrosis in diabetic and non-diabetic kidney injury. Additionally, their anti-inflammatory effects extend toothers like non-alcoholic fatty liver disease and inflammatory bowel disease. Collectively, SGLT2 inhibitors exhibit multi-organ protective potential through macrophage modulation, positioning them as promising immunomodulatory agents beyond glucose-lowering therapy.
{"title":"Pleiotropic effects of SGLT2 inhibitors: A focus on macrophage-mediated action","authors":"Bing Shu , Xisha Chen , Zhonghao Liu , Huifang Tang , Bo Yang , Chengxiao Fu","doi":"10.1016/j.phrs.2025.108046","DOIUrl":"10.1016/j.phrs.2025.108046","url":null,"abstract":"<div><div>SGLT2 inhibitors, initially developed for type 2 diabetes management, have primarily demonstrated pleiotropic benefits in cardiovascular, renal, pulmonary, digestive and endocrine/metabolic, et al. Emerging evidence highlights their immunomodulatory effects on macrophages, key players in disease pathogenesis. This review summarizes the mechanisms by which dapagliflozin, empagliflozin, and canagliflozin regulate macrophage polarization, metabolic reprogramming, and inflammatory responses. These drugs suppress pro-inflammatory M1 macrophage activation, promote anti-inflammatory M2 phenotypes, and reduce the release of cytokines (e.g., IL-1β, IL-6,TNF-α) through pathways such as NF-κB, AMPK/mTOR, and JAK/STAT. In cardiovascular diseases, they attenuate atherosclerosis (AS) and myocardial fibrosis by limiting macrophage infiltration and foam cell formation. Renal protection is mediated via reduced macrophage-driven inflammation and fibrosis in diabetic and non-diabetic kidney injury. Additionally, their anti-inflammatory effects extend toothers like non-alcoholic fatty liver disease and inflammatory bowel disease. Collectively, SGLT2 inhibitors exhibit multi-organ protective potential through macrophage modulation, positioning them as promising immunomodulatory agents beyond glucose-lowering therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108046"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597124","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 : 2025-12-01DOI: 10.1016/j.phrs.2025.108057
Lena-Sophie Menig-Benzig , Viktoria Stühler , Pascale Mazzola , Hannah Heinrich , Ute Hofmann , Natalie Widmann , Regina Bohnert , Sylvia K. Neef , Carolin Sauter-Meyerhoff , Christian Schmees , Anika Fuhr , Verena Klumpp , Steffen Rausch , Dennis Gürgen , Thomas E. Mürdter , Stefan Winter , Florian A. Büttner , Stephan Kruck , Anaïs Choffart , André F. Martins , Elke Schaeffeler
Clear cell renal cell carcinoma (ccRCC) is characterized by a metabolic shift towards enhanced aerobic glycolysis and increased lactate production. The survival rate for metastatic RCC is still poor. We evaluated the lactate monocarboxylate transporter 4 (MCT4), encoded by SLC16A3, as drug target for metastatic disease. MCT4 protein expression in 209 distant ccRCC metastases, including 40 recurrent metastases, was generally as high as compared to primary tumor tissue and significantly increased compared to non-tumor tissue (P < 1E-15). MCT4 expression was irrespective of affected organs and mutations in RCC driver genes. DNA methylation in the SLC16A3 promoter, assessed by MALDI TOF mass spectrometry and correlated with clinicopathological data, were not significantly different in metastases of all investigated organ sites, and between paired tumor and metastases samples. Visualization of expression in single-cell and spatial RNA sequencing datasets reveals main expression of SLC16A3 in cells derived from tumor, tumor-normal interface, metastatic and lymph node tissue. Alone or combined with inhibition of mitochondrial respiration by metformin and phenformin, the MCT4 inhibitor syrosingopine significantly inhibits lactate efflux, induces cell viability reduction in four different RCC cell lines and patient-derived 2D/3D models, and alterations in cellular metabolism and mitochondrial respiration. Six patient-derived RCC air-liquid interface models, mimicking the complex RCC architecture, corroborate these data. Beyond potential prediction of patient outcome using MCT4 expression and DNA methylation at specific CpG sites, drug targeting of MCT4 and inhibiting mitochondrial respiration synergistically is a novel treatment strategy for metastatic ccRCC.
{"title":"Drug targeting of the monocarboxylate transporter MCT4 is a novel treatment strategy for metastatic ccRCC","authors":"Lena-Sophie Menig-Benzig , Viktoria Stühler , Pascale Mazzola , Hannah Heinrich , Ute Hofmann , Natalie Widmann , Regina Bohnert , Sylvia K. Neef , Carolin Sauter-Meyerhoff , Christian Schmees , Anika Fuhr , Verena Klumpp , Steffen Rausch , Dennis Gürgen , Thomas E. Mürdter , Stefan Winter , Florian A. Büttner , Stephan Kruck , Anaïs Choffart , André F. Martins , Elke Schaeffeler","doi":"10.1016/j.phrs.2025.108057","DOIUrl":"10.1016/j.phrs.2025.108057","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC) is characterized by a metabolic shift towards enhanced aerobic glycolysis and increased lactate production. The survival rate for metastatic RCC is still poor. We evaluated the lactate monocarboxylate transporter 4 (MCT4), encoded by <em>SLC16A3</em>, as drug target for metastatic disease. MCT4 protein expression in 209 distant ccRCC metastases, including 40 recurrent metastases, was generally as high as compared to primary tumor tissue and significantly increased compared to non-tumor tissue (P < 1E-15). MCT4 expression was irrespective of affected organs and mutations in RCC driver genes. DNA methylation in the <em>SLC16A3</em> promoter, assessed by MALDI TOF mass spectrometry and correlated with clinicopathological data, were not significantly different in metastases of all investigated organ sites, and between paired tumor and metastases samples. Visualization of expression in single-cell and spatial RNA sequencing datasets reveals main expression of SLC16A3 in cells derived from tumor, tumor-normal interface, metastatic and lymph node tissue. Alone or combined with inhibition of mitochondrial respiration by metformin and phenformin, the MCT4 inhibitor syrosingopine significantly inhibits lactate efflux, induces cell viability reduction in four different RCC cell lines and patient-derived 2D/3D models, and alterations in cellular metabolism and mitochondrial respiration. Six patient-derived RCC air-liquid interface models, mimicking the complex RCC architecture, corroborate these data. Beyond potential prediction of patient outcome using MCT4 expression and DNA methylation at specific CpG sites, drug targeting of MCT4 and inhibiting mitochondrial respiration synergistically is a novel treatment strategy for metastatic ccRCC.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108057"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687868","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 : 2025-12-01DOI: 10.1016/j.phrs.2025.108059
Sara Ibgui , Daisy Lints , Simon Milling
Inflammatory bowel disease (IBD) is an idiopathic condition characterised by chronic relapsing intestinal inflammation, affecting approximately 6.8 million people globally. Crohn’s disease and ulcerative colitis are two main subtypes. The microbiota in IBD patients has been extensively researched, and dysbiosis is associated with IBD onset. While current treatments reduce morbidity and improve the quality of life of IBD patients, they have strong anti-inflammatory effects, creating an immunosuppressed environment and increase the risk of comorbidities, highlighting the need for better therapeutics. The gut-brain axis (GBA) communication pathway allows bidirectional neural, hormonal, metabolic, immunological and microbial signalling. This review investigates the signalling pathways across the GBA and explores how dysbiosis, neuroinflammation and serotonergic dysregulation are interlinked and may contribute to IBD pathogenesis and neurological comorbidities. Focusing on the immunomodulation of serotonergic signalling and proposed mechanisms of action of psychotropic drugs, including antidepressants and psychedelic compounds, we highlight the serotonergic signalling pathway as a potential novel therapeutic target for IBD combination therapy.
{"title":"From the gut to the brain: Potential novel avenues for IBD treatment via serotonergic pathways","authors":"Sara Ibgui , Daisy Lints , Simon Milling","doi":"10.1016/j.phrs.2025.108059","DOIUrl":"10.1016/j.phrs.2025.108059","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is an idiopathic condition characterised by chronic relapsing intestinal inflammation, affecting approximately 6.8 million people globally. Crohn’s disease and ulcerative colitis are two main subtypes. The microbiota in IBD patients has been extensively researched, and dysbiosis is associated with IBD onset. While current treatments reduce morbidity and improve the quality of life of IBD patients, they have strong anti-inflammatory effects, creating an immunosuppressed environment and increase the risk of comorbidities, highlighting the need for better therapeutics. The gut-brain axis (GBA) communication pathway allows bidirectional neural, hormonal, metabolic, immunological and microbial signalling. This review investigates the signalling pathways across the GBA and explores how dysbiosis, neuroinflammation and serotonergic dysregulation are interlinked and may contribute to IBD pathogenesis and neurological comorbidities. Focusing on the immunomodulation of serotonergic signalling and proposed mechanisms of action of psychotropic drugs, including antidepressants and psychedelic compounds, we highlight the serotonergic signalling pathway as a potential novel therapeutic target for IBD combination therapy.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108059"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145708996","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 : 2025-12-01DOI: 10.1016/j.phrs.2025.108043
Chenrong Jin , Juhui Qiao , Huilin Gong , Xiaorui Yu , Xinran Wang , Jiao Xi , Runying Mi , Shiting Yu , Daian Pan , Siming Wang , Xiaolin Tong , Daqing Zhao , Meichen Liu
Aging profoundly impacts the brain, serving as a primary driver of neurodegenerative diseases through mechanisms closely linked to mitochondrial dysfunction. Despite its clinical significance, the molecular mechanisms remain unclear, and safe, effective therapies are urgently needed. Here, leveraging ginseng's neuroprotective potential, we screened for blood-brain barrier-permeable saponins with optimal neuroprotective efficacy and identified ginsenoside Re (Re) as the predominant mitochondrially targeted neuroprotective saponin. Midlife Reintervention, temporally aligned with the natural window of mitochondrial hyperfusion, rescued age-related degenerative pathology in Drosophila. Re administration ameliorated dopaminergic neuron loss, mitigated muscles pathology, improved cognitive-motor deficits, and extended healthspan. Mechanistic studies revealed that Re directly binds to the Drp1 across multiple species via the highly conserved L94 residue, triggering robust S616 phosphorylation that drives Drp1 translocation to mitochondria, thereby restoring fission-fusion equilibrium. Re further spatiotemporally coupled fission-mitophagy through the Drp1-Atg1/ULK1 axis, enabling autophagosome initiation and ensuring efficient clearance of damaged organelles. This dual regulation enhanced bioenergetic capacity and delayed functional decline. Genetic ablation of Drp1 L94 completely abolished Re's benefits, while translational studies in mice confirmed that healthspan extension required intact Drp1-L94 functionality. Notably, Re demonstrated conserved neuroprotective efficacy in both human induced pluripotent stem cells-derived dopaminergic neurons and Drosophila Parkinson's model, indicating preservation of the Drp1-mitophagy pathway across species. Our findings establish Re as a geroprotector that targets the conserved Drp1-L94 residue to restore mitochondrial homeostasis. By spatiotemporally coupling fission to Atg1-mediated mitophagy during the critical midlife hyperfusion window, Re delays neurodegeneration, thereby establishing a molecular basis for developing therapies against age-related decline.
{"title":"Ginsenoside Re binds Drp1 Leu94 across species to restore mitochondrial homeostasis via Atg1/ULK1-dependent fission-mitophagy coupling in age-related degeneration","authors":"Chenrong Jin , Juhui Qiao , Huilin Gong , Xiaorui Yu , Xinran Wang , Jiao Xi , Runying Mi , Shiting Yu , Daian Pan , Siming Wang , Xiaolin Tong , Daqing Zhao , Meichen Liu","doi":"10.1016/j.phrs.2025.108043","DOIUrl":"10.1016/j.phrs.2025.108043","url":null,"abstract":"<div><div>Aging profoundly impacts the brain, serving as a primary driver of neurodegenerative diseases through mechanisms closely linked to mitochondrial dysfunction. Despite its clinical significance, the molecular mechanisms remain unclear, and safe, effective therapies are urgently needed. Here, leveraging ginseng's neuroprotective potential, we screened for blood-brain barrier-permeable saponins with optimal neuroprotective efficacy and identified ginsenoside Re (Re) as the predominant mitochondrially targeted neuroprotective saponin. Midlife Reintervention, temporally aligned with the natural window of mitochondrial hyperfusion, rescued age-related degenerative pathology in <em>Drosophila</em>. Re administration ameliorated dopaminergic neuron loss, mitigated muscles pathology, improved cognitive-motor deficits, and extended healthspan. Mechanistic studies revealed that Re directly binds to the Drp1 across multiple species via the highly conserved L94 residue, triggering robust S616 phosphorylation that drives Drp1 translocation to mitochondria, thereby restoring fission-fusion equilibrium. Re further spatiotemporally coupled fission-mitophagy through the Drp1-Atg1/ULK1 axis, enabling autophagosome initiation and ensuring efficient clearance of damaged organelles. This dual regulation enhanced bioenergetic capacity and delayed functional decline. Genetic ablation of Drp1 L94 completely abolished Re's benefits, while translational studies in mice confirmed that healthspan extension required intact Drp1-L94 functionality. Notably, Re demonstrated conserved neuroprotective efficacy in both human induced pluripotent stem cells-derived dopaminergic neurons and <em>Drosophila</em> Parkinson's model, indicating preservation of the Drp1-mitophagy pathway across species. Our findings establish Re as a geroprotector that targets the conserved Drp1-L94 residue to restore mitochondrial homeostasis. By spatiotemporally coupling fission to Atg1-mediated mitophagy during the critical midlife hyperfusion window, Re delays neurodegeneration, thereby establishing a molecular basis for developing therapies against age-related decline.</div></div>","PeriodicalId":19918,"journal":{"name":"Pharmacological research","volume":"222 ","pages":"Article 108043"},"PeriodicalIF":10.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588284","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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