Zhou Z, Cutts R, Hrebien S
… +10 more, Zhang CX, Garcia-Murillas I, Zhang WZ, Frankell AM, Cooper WN, Roshan A, Turner NC, Kaplan T, Rosenfeld N, Zhao H
EMBO Mol Med
· 2026 Apr · PMID 41857451
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Methods to detect circulating tumor DNA (ctDNA) enable minimally invasive responsive monitoring of cancer dynamics. However, sensitive and cost-effective methods are still lacking. Current methods for detecting cancer si...Methods to detect circulating tumor DNA (ctDNA) enable minimally invasive responsive monitoring of cancer dynamics. However, sensitive and cost-effective methods are still lacking. Current methods for detecting cancer signals in shallow whole-genome sequencing (sWGS) data from cell-free DNA (cfDNA) via copy number aberration (CNA) analysis typically have a limit of detection of approximately 3% tumor fraction (TF). We developed informCNA, a bioinformatics method that leverages CNA information from sWGS of tumor or pre-treatment plasma samples with high TF as references, enabling ctDNA detection down to 0.2% TF across multiple cancer types. In 177 serial plasma samples from 18 patients with ovarian cancer, informCNA showed high concordance with the standard serum protein marker CA-125 and identified recurrence a median of 3.7 months earlier than CA-125 test. These results demonstrate the potential of personalized CNA analysis through sWGS for estimating ctDNA burden, enabling precise and cost-effective disease monitoring and early detection of relapse.
Barinberg D, Sebald H, Gold T
… +10 more, Rai B, Radtke D, Lerm D, Voehringer D, Jantsch J, Wirtz S, Antonova AU, Colonna M, Bogdan C, Schleicher U
EMBO Mol Med
· 2026 Apr · PMID 41813911
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Eosinophils exhibit antimicrobial, cytotoxic and immunoregulatory effects, but our knowledge of their transcriptional and functional heterogeneity is still limited, especially in non-intestinal tissues. Here, we used a m...Eosinophils exhibit antimicrobial, cytotoxic and immunoregulatory effects, but our knowledge of their transcriptional and functional heterogeneity is still limited, especially in non-intestinal tissues. Here, we used a mouse model of chronic cutaneous inflammation elicited by the protozoan pathogen Leishmania mexicana to investigate the function and transcriptional dynamics of skin eosinophils. Infection of C57BL/6 mice triggered local and systemic eosinophilia that was driven by type 2 innate lymphoid cells and interleukin-5. Genetic and pharmacological eosinophil depletion led to an enhanced Th1 response, polarization towards M1-like macrophages and resolution of clinical disease, despite an unexpected simultaneous upregulation of IL-4. Single-cell transcriptomics revealed a skin-imprinted trajectory of inflammatory eosinophils that strongly expressed the glucose transporter Slc2a3 (GLUT3) These eosinophils impeded the function of Th1 cells by forming a competitive metabolic niche through preferential glucose uptake. Our findings uncover an inflammatory, metabolically reprogrammed eosinophil population that promotes chronic skin inflammation by limiting protective T cell responses.
Guo S, Jin H, Sun H
… +9 more, Huang S, Chen Y, Chang Y, Zhang Y, Ding L, Chen S, Fu C, Yin Y, Cheng W
EMBO Mol Med
· 2026 Apr · PMID 41807703
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Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). How...Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.
Zhang W, Allen EK, Li S
… +19 more, Tarasova I, Farrukee R, Kedzierski L, Gilbertson B, McQuilten HA, Habel JR, Allen LF, Rockman S, Londrigan SL, Kent SJ, Wheatley AK, Trubiano JA, Kotsimbos TC, Cheng AC, Schroeder J, Crawford JC, Thomas PG, Kedzierska K, Nguyen THO
EMBO Mol Med
· 2026 Apr · PMID 41803327
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Influenza viruses continue to cause a substantial global disease burden. Despite influenza vaccination, some individuals succumb to life-threatening influenza or death. Yet our understanding of immune features elicited b...Influenza viruses continue to cause a substantial global disease burden. Despite influenza vaccination, some individuals succumb to life-threatening influenza or death. Yet our understanding of immune features elicited by vaccination and influenza A and B virus (IAV, IBV) infection is limited. To define molecular signatures of influenza-specific B-cells, we performed scRNA-sequencing of influenza-specific B-cells in vaccinees and hospitalized IAV/IBV-infected patients using HA-probes. We observed increased interferon-stimulated gene signatures (IF44L, IFITM1 and XAF1), in total B-cells from IBV-patients, but not at 1-month following patients' recovery or in IAV-patients or vaccinees. Phenotypic differentiation and isotype class-switching of HA-specific B-cells were observed following vaccination, with clonal sharing between memory and atypical B-cell phenotypes. In-vitro influenza virus infection experiments showed IBVs having higher infectivity of human PBMCs, including B-cells, and reduced B-cell proliferation compared to IAV, potentially associated with antiproliferative effect of IFITM1. We provide key insights into B-cell immunity towards IBV and IAV infections and vaccination, which will inform rational vaccine design and therapeutic strategies aimed at eliciting robust HA-specific B-cell responses, while minimizing adverse effects caused by natural infection.
Richardson SA, Safrastyan A, Karimpour M
… +13 more, Gulati G, Harker PJB, Redfern A, Pearce SP, Makeev VJ, Brennan B, Lee ATJ, Clipson A, Hill SM, Dive C, Rothwell DG, McCabe MG, Mouliere F
EMBO Mol Med
· 2026 Apr · PMID 41792463
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Liquid biopsies and cell-free DNA (cfDNA) offer minimally invasive methods for the diagnosis and monitoring of Ewing Sarcoma (EwS). EwS have a low tumour mutational burden and their detection with plasma cfDNA is challen...Liquid biopsies and cell-free DNA (cfDNA) offer minimally invasive methods for the diagnosis and monitoring of Ewing Sarcoma (EwS). EwS have a low tumour mutational burden and their detection with plasma cfDNA is challenging. We hypothesised that analysing the cfDNA methylome and fragmentome could enhance sensitivity for detecting EwS and identifying disease recurrence. Using T7-MBD-seq, we conducted whole-genome and methylome sequencing of cfDNA from 87 serial samples of 23 patients with EwS and 3 patients with CIC-rearranged sarcoma (CIC). With EwingSign, a new machine learning model, we identified EwS or CIC in a test set for 11 out of 16 patients at diagnosis and 15 out of 18 clinically confirmed relapse events. 0 out of 24 non-cancer controls (NCC) were detected positive with EwingSign. When combined with global and regional fragmentome analysis, all 18 relapse cases were detected, with 15/18 detected by 2 or more modalities, and 1 out of 24 NCC was detected by one modality. These findings indicate that cfDNA methylome and fragmentome analysis, if validated in a larger cohort, could improve disease detection, monitoring and relapse identification in patients with EwS.
Alam N, Wolfle C, Butkeviciute E
… +3 more, Quinkert D, King LDW, Higgins MK
EMBO Mol Med
· 2026 Mar · PMID 41772083
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Effective vaccines against malaria are urgently required. All components of the PfPCRCR complex are essential for erythrocyte invasion by Plasmodium falciparum and are potential vaccine immunogens against blood-stage mal...Effective vaccines against malaria are urgently required. All components of the PfPCRCR complex are essential for erythrocyte invasion by Plasmodium falciparum and are potential vaccine immunogens against blood-stage malaria. Of these, PfRH5 has progressed furthest in clinical development, while PfCyRPA also induces parasite growth-inhibitory antibodies. Here, we used direct nanoparticle coupling and structure-guided design to generate improved PfCyRPA-based immunogens. PfCyRPA is a six-bladed β-propeller. Blades 1 and 2 are exposed in the PfPCRCR complex and contain the epitopes of the most potent known growth-inhibitory antibodies. We therefore performed structure-guided design to generate a correctly folded, thermostable epitope mimic, PfCyRPA-EM, containing blades 1 and 2. In a pre-clinical model, PfCyRPA-EM elicited antibodies that inhibited parasite growth at lower concentrations than those elicited by PfCyRPA. In addition, the higher thermostability of PfCyRPA-EM and its improved expression as an I53-50 nanoparticle fusion make it well-suited for clinical development, alone or with other immunogens.
EMBO Mol Med
· 2026 Apr · PMID 41760956
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In this Correspondence, H. Behrens and colleagues show that the potentiating effect of the small molecule 5-aminolaevulinic acid (5-ALA) on the activity of artemisinin observed in cancer does not translate to malaria par...In this Correspondence, H. Behrens and colleagues show that the potentiating effect of the small molecule 5-aminolaevulinic acid (5-ALA) on the activity of artemisinin observed in cancer does not translate to malaria parasites. Thus, co-administration of artemisinin and 5-ALA does not seem to be a promising strategy to improve malaria treatment. [Image: see text]
Chimata P, Lall S, Annilo T
… +4 more, Mathew MK, Metspalu A, Shenthar J, Dhandapany PS
EMBO Mol Med
· 2026 Apr · PMID 41735622
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Dilated cardiomyopathy (DCM) is a heart condition characterized by systolic and diastolic dysfunction. In many instances, patients with DCM coexist with obesity and sleep apnea. It is unclear whether genetic variants con...Dilated cardiomyopathy (DCM) is a heart condition characterized by systolic and diastolic dysfunction. In many instances, patients with DCM coexist with obesity and sleep apnea. It is unclear whether genetic variants contribute to the combined phenotypes of DCM, obesity, and sleep apnea. Here, using next-generation sequencing, we identified pathogenic KCNA2 variants in patients of diverse ancestry with DCM, Obesity, and Sleep Apnea (termed DOSA). Electrophysiological and biochemical assays using biosensors revealed loss of membrane current due to trafficking defects in cells expressing KCNA2 variants. Furthermore, cellular models including patient-specific iPSC cardiomyocytes and organoid models displayed RAC1-ERK1/2 hyperactivation in disease pathogenesis. A Drosophila model expressing KCNA2 variant showed DOSA-like phenotypes which was rescued using RAC1 inhibitors. Our results provide the first evidence that KCNA2 variants can lead to DOSA phenotypes, further expanding the genetic regulatory roles of potassium channels in human diseases.
Müller F, McLachlan E, Costa AC
… +14 more, Qu J, Shrestha B, Wang Z, De Virgiliis F, Hutson TH, Zhou L, Kong G, Chadwick JS, La Montanara P, Yuan Z, Haberman N, Sousa MM, Palmisano I, Di Giovanni S
EMBO Mol Med
· 2026 Apr · PMID 41731079
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Neuronal maturation involves a tightly regulated cessation of growth and acquisition of polarity, ultimately leading to synapse formation. While essential for circuit stability, maturation marks the loss of regenerative...Neuronal maturation involves a tightly regulated cessation of growth and acquisition of polarity, ultimately leading to synapse formation. While essential for circuit stability, maturation marks the loss of regenerative capacity after central nervous system (CNS) injury. The molecular programs coupling maturation to regenerative decline remain incompletely understood. Here, we show that the transcriptional and epigenetic signatures enabling axon growth in dorsal root ganglion (DRG) neurons are lost as they transition from immature, non-polarized cells to mature, pseudo-unipolar neurons. We identify the transcriptional co-regulator CITED2 as a key epigenetic switch, active in immature and regenerating DRG neurons but silent after non-regenerative spinal cord injury (SCI). Cited2 overexpression reactivates growth programs, enhancing regeneration in vivo after SCI. Mechanistically, CITED2 reinstates developmental epigenetic and transcriptional profiles, decoupling maturation from regenerative failure. Pharmacogenomic screening identified CITED2 as a target of the clinically approved HDAC inhibitor Panobinostat, which promoted axonal growth, sprouting, and functional recovery post-injury. These findings position CITED2 as a key regulator of sensory neuron plasticity and a novel therapeutic target for CNS repair.
Gorzkiewicz M, Noseir S, Vengurlekar M
… +16 more, Ghosh M, Katahira I, Abromavičiūtė D, Gerling-Driessen U, Bonda L, Rähse N, Lapsien M, Bockholt S, Bergmann AK, Kostadinovska K, Fraii H, Lang KS, Oestereich L, Gohlke H, Hartmann L, Lang PA
EMBO Mol Med
· 2026 Apr · PMID 41731078
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Viral infections remain a major challenge due to the limited availability and efficacy of current treatments. Existing antivirals primarily target viral replication but are often virus-specific and can lead to drug resis...Viral infections remain a major challenge due to the limited availability and efficacy of current treatments. Existing antivirals primarily target viral replication but are often virus-specific and can lead to drug resistance. Sulfated glycosaminoglycans (GAGs) have emerged as promising broad-spectrum agents that block viral binding and entry into host cells. Here, we show that highly sulfated GAGs restrict the infectivity of both pathogenic and non-pathogenic Arenaviruses. Using the lymphocytic choriomeningitis virus (LCMV) model, we demonstrate that GAG exposure reduces viral entry and infection in cell lines and bone marrow-derived dendritic cells, impairing their ability to activate antiviral T cells. In vivo, early exposure of LCMV to dextran sulfate suppressed immune activation, leading to diminished T-cell responses, prolonged infection, and increased immunopathology. By contrast, administering dextran sulfate during the acute infection phase decreased viral load, improved effector T-cell function, and reduced liver pathology. These findings highlight the therapeutic potential of sulfated GAGs against Arenavirus infections and the importance of treatment timing for clinical efficacy.
Llamazares-Prada M, Schwartz U, Pease DF
… +24 more, Pohl ST, Ackesson D, Li R, Behrendt A, Tamas R, Stammler V, Richter M, Muley T, Scherer M, Hey J, Espinet E, Heußel CP, Warth A, Schneider MA, Winter H, Herth FJ, Imbusch CD, Brors B, Benes V, Wyatt D, Jurkowski TP, Stahl HF, Plass C, Jurkowska RZ
EMBO Mol Med
· 2026 Apr · PMID 41731077
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Altered respiratory barrier integrity and impaired lung regeneration are hallmarks of chronic obstructive pulmonary disease (COPD). To investigate the molecular mechanisms driving the impaired regeneration of alveolar ep...Altered respiratory barrier integrity and impaired lung regeneration are hallmarks of chronic obstructive pulmonary disease (COPD). To investigate the molecular mechanisms driving the impaired regeneration of alveolar epithelial progenitors in COPD, we generated whole-genome DNA methylation and transcriptome maps of sorted human primary alveolar type 2 cells (AT2) at different disease stages. Our analysis revealed aberrant DNA methylation at specific gene promoters in AT2 during COPD, which was anticorrelated with gene expression changes. Interferon signaling was the top-upregulated pathway in COPD, associated with a concomitant loss of promoter-proximal DNA methylation. Integrated pathway analysis revealed transcription factor IRF9 as the master regulator of interferon signaling in COPD. Epigenetic regulation of the interferon pathway was validated by targeted DNA demethylation of the IRF9 gene, mimicking the effects observed in COPD-derived AT2. Our findings suggest that COPD-associated DNA methylation alterations in AT2 cells may impair internal regeneration programs in lung parenchyma.
Perdigão C, Torres J, Magnussen HM
… +17 more, Koch J, Rudashevskaya E, Moschref F, Fiosins M, Benseler F, Wenger S, Nilsson T, Beuermann S, Bonn S, Rizzoli SO, Kulathu Y, Jahn O, Cooper BH, Ambrozkiewicz MC, Rhee J, Brose N, Tirard M
EMBO Mol Med
· 2026 Apr · PMID 41731076
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Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation deficiencies cause select...Genetic variants that hinder post-translational protein modifications by UFM1, UFMylation, cause encephalopathies. UFMylation regulates endoplasmic reticulum (ER) homeostasis, but how UFMylation deficiencies cause selective neurological defects is unknown. Using murine UFM1-deficient neurons, we investigated two types of UFMylation pathologies, UFM1 loss and expression of a pathogenic UFM1-R81C variant. We found that UFM1-deficiency confounds neuron development and synapse function. Mechanistically, UFM1 loss is associated with induction of ER stress, activation of the unfolded protein response (UPR) pathway, and reduced protein translation. These defects are rescued by wild-type UFM1, but only partially by UFM1-R81C. UFM1-deficient and UFM1-R81C-expressing neurons display distinct responses to ER stress, indicating that UFM1-R81C is not merely a loss-of-function variant. Exploring therapeutic options, we show that Trazodone, an inhibitor of the UPR, restores protein translation solely in UFM1-R81C-expressing neurons, and increases synapse numbers in both UFM1-KO and UFM1-R81C-expressing neurons. Our study unveils a pivotal role for UFMylation in neuronal development, provides a molecular understanding of the signaling mechanisms altered in UFM1-associated encephalopathies, and offers important insights into potential treatments for these disorders.
Wu R, Khosraviani N, Mansur A
… +12 more, Boudreau E, Largoza GE, Park S, Gustafson D, Raju S, Ching C, Klip A, Wälchli T, Howe KL, Radovanovic I, Wythe JD, Fish JE
EMBO Mol Med
· 2026 Mar · PMID 41708990
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Somatic activating KRAS mutations in endothelial cells are the predominant cause of sporadic brain arteriovenous malformations (bAVMs) and also occur in sporadic extracranial AVMs. We found that KRAS expression in the en...Somatic activating KRAS mutations in endothelial cells are the predominant cause of sporadic brain arteriovenous malformations (bAVMs) and also occur in sporadic extracranial AVMs. We found that KRAS expression in the endothelium increased angiogenesis, which was accompanied by enhanced glucose uptake and glycolytic flux. Mechanistically, this increase in glycolysis was facilitated by enhanced membrane localization of glucose transporters (e.g., GLUT1) and induction of hexokinase-2 (HK2) expression. Importantly, RNA-sequencing and proteomics revealed that HK2 appeared to be the only glycolytic component elevated. Analysis of single-cell RNA-sequencing data and immunofluorescence staining confirmed that HK2 was elevated in mouse and human bAVMs. Critically, either pharmacologic inhibition of glycolytic flux or knockdown of HK2 suppressed sprouting angiogenesis in cultured KRAS endothelial cells. Glycolysis inhibition also reversed arteriovenous shunts and potentiated the effect of MEK inhibition in a KRAS-mutant zebrafish model. Finally, combined glycolysis and MEK inhibition suppressed angiogenesis in patient-derived bAVM primary endothelial cells. Together, our findings show that KRAS-driven reprogramming of endothelial metabolism represents a potential therapeutic vulnerability for sporadic AVMs.
EMBO Mol Med
· 2026 Mar · PMID 41708989
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Brain arteriovenous malformations (bAVMs) are vascular anomalies characterized by a knot of intertwined and enlarged blood vessels. They form atypical direct connections (shunts) between the arterial and venous sides of...Brain arteriovenous malformations (bAVMs) are vascular anomalies characterized by a knot of intertwined and enlarged blood vessels. They form atypical direct connections (shunts) between the arterial and venous sides of the circulation, bypassing the capillary bed. This pathological flow pattern exposes fragile veins to excess mechanical stress, predisposing them to rupture. Although the incidence of bAVMs is low, their clinical impact is substantial as rupture results in intracranial hemorrhage, which often leads to severe neurological consequences including stroke (Samaniego et al, 2024).
Tong L, Song H, Gao Y
… +12 more, Qin D, Wang C, Li Q, Fu Y, Zhao C, Ying Z, Chen D, Gao C, Han C, Zhao W, Qin Y, Zhang L
EMBO Mol Med
· 2026 Mar · PMID 41703092
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NLRP3 inflammasome, the archetypical molecular driver of inflammation, plays crucial roles in host defense and maintaining cellular homeostasis. Demethylation of histone 3 lysine 9 trimethylation (H3K9me3, the repressive...NLRP3 inflammasome, the archetypical molecular driver of inflammation, plays crucial roles in host defense and maintaining cellular homeostasis. Demethylation of histone 3 lysine 9 trimethylation (H3K9me3, the repressive mark for euchromatic genes) is essential for activating gene transcription. However, whether H3K9 demethylation is required for the induction of proinflammatory cytokines remains largely unknown. Here, we show that histone demethylase lysine-specific demethylase 4B (KDM4B) mediates H3K9me3 demethylation at the Nlrp3 promoter to induce NLRP3 expression, thereby selectively enhancing NLRP3 inflammasome activation without affecting NF-κB activation. Concordantly, both Kdm4b deficiency and the selective KDM4 inhibitor ML324 inhibit NLRP3 inflammasome activation and ameliorate NLRP3-dependent inflammatory diseases in vivo. Furthermore, high glucose level upregulates KDM4B, promoting NLRP3 inflammasome activation and IL-1β secretion, thus aggravating aberrant inflammation during viral infections. Our findings reveal the role of H3K9me3 demethylation in initiating inflammation, identify KDM4B as an epigenetic accelerator of NLRP3, and propose that modulating H3K9me3 could represent a targeted anti-inflammatory strategy.
EMBO Mol Med
· 2026 Mar · PMID 41699260
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Effective therapeutic strategies for influenza, ranging from seasonal flu outbreaks to sporadic pandemics, should ideally combine antiviral efficacy to accelerate viral clearance with targeted immunomodulation to mitigat...Effective therapeutic strategies for influenza, ranging from seasonal flu outbreaks to sporadic pandemics, should ideally combine antiviral efficacy to accelerate viral clearance with targeted immunomodulation to mitigate excessive inflammation. In this issue of , Cezard et al introduce the inhibitory potential of the tricarboxylic acid (TCA) cycle intermediate cis-aconitate against influenza virus. Cis-aconitate is promising for further translational evaluation, as it meets the dual targeting criteria of antiviral and anti-inflammatory activity at both early as well as late stages of infection. Remarkably, these effects occur independently of its conversion into itaconate, a well-characterized immunomodulatory TCA derivative. This novel aspect of cis-aconitate further supports continued consideration of TCA cycle intermediates beyond their canonical metabolic roles.
Cezard A, Brea-Diakite D, Vasseur V
… +26 more, Wacquiez A, Gonzalez L, Le Goffic R, Da Costa B, Tinard A, Fouquenet D, Heumel S, Machelart A, Hoffmann E, Brodin P, Trottein F, Mathieu C, Canus L, Jacolin F, Vidalain PO, Perrin-Cocon L, Lotteau V, Burlaud-Gaillard J, Tertigas D, Surette MG, Legras A, Sizaret D, Baranek T, Paget C, Guillon A, Si-Tahar M
EMBO Mol Med
· 2026 Mar · PMID 41699259
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The influenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therap...The influenza virus poses a significant global health challenge, causing approximately 500,000 deaths annually. Its ability to evade antiviral treatments and vaccine-induced immunity underscores the need for novel therapeutic approaches. Our study identifies cis-aconitate (cis-aco), a mitochondria-derived metabolite, as a potent dual-action agent against influenza, independently of its metabolic derivative, itaconate. Cis-aco impairs viral polymerase activity, resulting in decreased viral mRNA expression and protein synthesis, as observed for the influenza A/Scotland/20/74 (H3N2) strain. This antiviral effect was further confirmed across multiple influenza A and B strains, as well as in ex vivo human airway and lung organotypic models. Beyond its antiviral properties, cis-aco exhibits potent anti-inflammatory effects, disrupting key inflammatory cascades and reducing the secretion of inflammatory mediators. In a mouse model of influenza pneumonia, cis-aco mitigates viral replication, inflammation, and immune cell activation, significantly improving survival. Notably, its efficacy persists even when administered at later stages of infection, when oseltamivir/Tamiflu® is no longer effective. These findings position cis-aco as a promising influenza treatment, combining antiviral and anti-inflammatory benefits within a clinically relevant timeframe.
Russo EE, Rezayof A, Wallace C
… +15 more, Williams EQ, Beerepoot P, Milenkovic M, Novalen M, Blundell A, Lipina TV, Locke J, Christian R, Finnie PSB, Edgar LJ, Tyndale RF, Watkins-Chow D, Ramsey AJ, Jones SR, Salahpour A
EMBO Mol Med
· 2026 Mar · PMID 41699258
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The dopamine transporter is essential for dopamine homeostasis maintenance. Therefore, single amino acid changes in its gene can be sufficient to induce disease, such as dopamine transporter deficiency syndrome (DTDS). D...The dopamine transporter is essential for dopamine homeostasis maintenance. Therefore, single amino acid changes in its gene can be sufficient to induce disease, such as dopamine transporter deficiency syndrome (DTDS). DTDS-associated variants may lead to DAT protein misfolding, retention in the endoplasmic reticulum, and reduced DAT surface expression. In turn, proper dopaminergic regulation is lost. Current treatments for DTDS are largely ineffective, necessitating better options. We developed a novel mouse model of DTDS harboring the A313V knock-in DAT variant, a proxy for the human A314V variant. The A313V mice are hyperactive, have decreased striatal tissue content of dopamine and increases in its metabolite HVA, and impaired dopamine uptake. FDA approved compounds alpha-methyl-para-tyrosine and amphetamine ameliorate the observed hyperactivity. Moreover, alpha-methyl-para-tyrosine may be a disease-modifying treatment by addressing the hyperdopaminergic tone underlying this hyperactivity. Noribogaine, a pharmacological chaperone for DAT, is unable to rescue DAT expression. These findings demonstrate that the A313V knock-in DAT variant mice recapitulate several defining phenotypes seen in patients with DTDS, and provide evidence for two novel treatments for the disease.
EMBO Mol Med
· 2026 Mar · PMID 41673122
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Endemic and emerging viral diseases continue to impose significant health, economic, and societal burdens worldwide. Vaccines and therapeutics represent two key pillars in the fight against these threats. Since the clini...Endemic and emerging viral diseases continue to impose significant health, economic, and societal burdens worldwide. Vaccines and therapeutics represent two key pillars in the fight against these threats. Since the clinical success of mRNA vaccines during the COVID-19 pandemic, mRNA therapeutics have rapidly evolved from a niche innovation into a validated and versatile medical platform. While early efforts focused primarily on vaccine development, recent advances have expanded the scope to antiviral applications of in vitro-transcribed mRNA. Emerging strategies include in vivo expression of neutralizing antibodies for passive immunization, delivery of innate immune effectors such as interferons and antiviral peptides, and programmable CRISPR-based antiviral systems. In parallel, progress in mRNA delivery technologies has enabled clinical translation, although challenges related to stability, specificity, and immunogenicity remain. In this Perspective article, we review recent preclinical and clinical advances in mRNA therapeutics for viral infections. We also highlight key scientific, technical, and regulatory challenges, and propose strategic solutions to address the pressing need for controlling endemic viral diseases and enhancing global pandemic preparedness.
Rahman NA, Singh S, Wiggins T
… +5 more, Santos MD, Moraski GC, Miller MJ, Berney M, Pethe K
EMBO Mol Med
· 2026 Mar · PMID 41652042
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Pretomanid is a unique anti-tuberculosis agent that inhibits both cell-wall synthesis and bioenergetics in Mycobacterium tuberculosis. While targeting the cell wall triggers a rapid bactericidal effect on replicating myc...Pretomanid is a unique anti-tuberculosis agent that inhibits both cell-wall synthesis and bioenergetics in Mycobacterium tuberculosis. While targeting the cell wall triggers a rapid bactericidal effect on replicating mycobacteria, the release of nitric oxide is linked to bactericidal potency against antibiotic-tolerant, non-replicating subpopulations through interference with the electron transport chain. Nonetheless, the specific molecular target(s) of the drug remain unknown. Through the utilization of genetic and chemical biology approaches, we present evidence that pretomanid inhibits both the cytochrome bcc:aa and bd oxidase respiratory branches. This property leads to a pronounced synergy with telacebec (Q203), a clinical-stage drug targeting the cytochrome bcc:aa, while concurrently curtailing the emergence of resistance to pretomanid. Furthermore, the incorporation of the cytochrome bd oxidase inhibitor ND-011992 resulted in a triple drug combination highly bactericidal against antibiotic-tolerant, non-replicating as well as replicating M. tuberculosis. The combination of pretomanid and drugs targeting the terminal oxidases holds the potential to serve as the cornerstone for an efficacious sterilizing drug regimen against tuberculosis.