Smits MJ, van Daal M, Verweij M
… +3 more, Nieuwenhuis E, Fuchs S, Jongsma KR
EMBO Mol Med
· 2026 May · PMID 41951917
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With rapid scientific advancements in gene-editing technologies, we advocate using the Accountability for Reasonableness (A4R) framework to guide priority setting of gene-editing research, ensuring equitable, efficient,...With rapid scientific advancements in gene-editing technologies, we advocate using the Accountability for Reasonableness (A4R) framework to guide priority setting of gene-editing research, ensuring equitable, efficient, consistent, and accountable translation of these revolutionizing innovations into society.
Schnappinger D, Berthel SJ, Boshoff HIM
… +20 more, Krieger IV, Sukheja P, Panda S, Rath S, Briggs K, Bian X, Rasheed S, Cleghorn LAT, Ghorpade S, Lamprecht DA, Fotouhi N, Müller R, Nathan C, Parish T, Rhee K, Warner P, McNamara CW, Rock JM, Sacchettini JC, Mizrahi V
EMBO Mol Med
· 2026 May · PMID 41946910
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Despite the approval of two first-in-class anti-tuberculars over the past two decades, the global burden of tuberculosis (TB) remains unacceptably high, in part due to the emergence and spread of drug-resistant strains o...Despite the approval of two first-in-class anti-tuberculars over the past two decades, the global burden of tuberculosis (TB) remains unacceptably high, in part due to the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). This review summarizes advances and ongoing challenges in anti-TB drug discovery, focusing on identifying and validating novel targets. Highlighted is a framework developed by the TB Drug Accelerator (TBDA) consortium for target validation in Mtb. Two computational platforms, DAIKON and PARSNIP, allow the systematic evaluation of targets across multiple dimensions, including chemical validation, genetic essentiality, vulnerability, and the feasibility to identify drug-like molecules for a target of interest. Case studies of Pks13 and NadE illustrate how these parameters guide target prioritization and risk assessment. By integrating these metrics, the framework enables dynamic, transparent target ranking, supporting development of both pan-TB and treatment-shortening regimens. This paradigm is adaptable to other bacterial pathogens and is designed to improve evidence-based decision-making in antibacterial drug discovery.
Wang Q, Ke X, Li E
… +8 more, Hong D, Cheng Z, Li H, Zhang J, Jin T, Gong R, Shu B, Chiu S
EMBO Mol Med
· 2026 May · PMID 41946909
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Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in infants and elderly individuals. Although nirsevimab represents a recent breakthrough against RSV infection, the emergen...Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in infants and elderly individuals. Although nirsevimab represents a recent breakthrough against RSV infection, the emergence of resistant variants highlight the need for additional antiviral strategies. Here, we report two nanobodies (Nbs), 1G9 and 1D8, that target the RSV fusion (F) protein and exhibit high neutralizing activity against RSV subtypes. In vivo, the Nbs-Fc demonstrated robust prophylactic and therapeutic efficacy. Cryo-electron microscopy revealed that 1G9 and 1D8 specifically engage a conformational pivot site within antigenic site IV, crosslinking the metastable heptad repeats B (HRB) and the conformationally stable domain II of the F protein. This interaction stabilizes the prefusion conformation and prevents the structural rearrangement required for membrane fusion. Notably, the binding residues are highly conserved across RSV subtypes, accounting for the broad-spectrum neutralization observed. Together, our findings identify a structurally conserved and functionally critical epitope on RSV F and highlight 1G9 and 1D8 as promising candidates for next-generation prophylactic and therapeutic interventions against RSV.
Xu J, Hao Y, Cao J
… +8 more, Yang X, Gao Y, Sun X, Nie R, Zhong Q, Zhong Y, Zhong J, Zheng T
EMBO Mol Med
· 2026 Jun · PMID 41942754
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High glucose impairs cognitive function in type 2 diabetes, but the underlying mechanism is unclear. In this study, guided by lactylome analysis, we reveal that high glucose induces LRPPRC K223 lactylation in hippocampal...High glucose impairs cognitive function in type 2 diabetes, but the underlying mechanism is unclear. In this study, guided by lactylome analysis, we reveal that high glucose induces LRPPRC K223 lactylation in hippocampal neurons by upregulating lactyltransferase AARS2, which weakens LRPPRC-SLIRP binding, reduces mitochondrial mRNA stability, subsequently leads to mitochondrial dysfunction, and ultimately results in neuronal apoptosis and cognitive decline. Notably, a novel short peptide designed to competitively inhibit LRPPRC K223 lactylation remarkably ameliorates cognitive impairment in diabetic mice. Moreover, through a large prospective cohort study, elevated plasma LRPPRC K224 lactylation (the human homolog of mouse LRPPRC K223) was identified as an independent predictor of cognitive impairment in type 2 diabetes patients. This work uncovers a key mechanism linking high glucose-induced lactylation to mitochondrial dysfunction and neuronal apoptosis, offering new molecular targets for prevention and treatment of diabetes-related cognitive impairment.
Bilusic M, Gannamedi DP, Challu B
… +7 more, Ferdous S, Mateo-Victoriano B, Pokharel S, Bayik D, Sharma J, Lombard DB, Rai P
EMBO Mol Med
· 2026 May · PMID 41942753
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Randomized clinical trials have highlighted the importance of weight control and exercise in improving cancer outcomes, yet the molecular mediators of these benefits remain poorly understood. Recent studies in Type 2 dia...Randomized clinical trials have highlighted the importance of weight control and exercise in improving cancer outcomes, yet the molecular mediators of these benefits remain poorly understood. Recent studies in Type 2 diabetic patients reported that the insulin-sensitizing drug, metformin, exerts its anorexigenic and anti-obesogenic effects through elevation of N-lactoyl-phenylalanine (Lac-Phe), a metabolite also reported to underlie the metabolic benefits of exercise in healthy individuals. Because metformin can be repurposed for oncology, we investigated whether the metformin/Lac-Phe link extends to cancer by profiling serum Lac-Phe levels in non-diabetic prostate cancer patients from BIMET-1, a prospective metformin trial, as well as those receiving metformin for metabolic dysfunction. Irrespective of disease stage, anticancer outcomes, or hormone therapy status, metformin treatment significantly and consistently increased serum Lac-Phe in these cancer patients to concentrations that approximated levels reported after strenuous exercise. Moreover, patients on the metformin arm of BIMET-1 exhibited improved weight management following anti-androgen therapy relative to those in the control group. By generalizing the metformin/Lac-Phe axis, our study provides a new molecular context for the metabolic benefits of repurposing metformin in cancer patients.
Tan GYT, Lin PY, Cheng LT
… +6 more, Tsai Yuan YS, Huang SH, Yu CA, Chen CT, Chi P, Hwang-Verslues WW
EMBO Mol Med
· 2026 May · PMID 41933240
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Ovarian clear cell carcinomas (OCCC), particularly cases that retain wild-type AT-rich interactive domain 1 A (ARID1A) expression (approximately 50% of the OCCC cases), are chemoresistant and lack specific therapies. We...Ovarian clear cell carcinomas (OCCC), particularly cases that retain wild-type AT-rich interactive domain 1 A (ARID1A) expression (approximately 50% of the OCCC cases), are chemoresistant and lack specific therapies. We identified BMAL2 as a critical OCCC oncogene that promotes tumorigenesis by preventing endogenous DNA damage. BMAL2 depletion altered the expression of genes encoding DNA damage repair proteins, including RAD51, a core enzyme of the homologous recombination (HR) pathway. This led to DNA double-stranded break accumulation, decreased cell viability and reduced tumor growth. This dependence on BMAL2 to maintain DNA integrity and cell viability can be a new route to suppress OCCC. Consistent with this idea, we found that GW833972A, a cannabinoid receptor agonist, bound BMAL2 with high affinity and facilitated its protein degradation. This in turn reduced RAD51 expression, leading to an accumulation of DNA damage, decreased cell viability and reduced OCCC tumor growth. GW833972A is effective by itself at high dose and can also be used at lower dosages to enhance the effectiveness of Poly (ADP-ribose) polymerase inhibitor (PARPi) treatments in BMAL2-expressing OCCC. Together, our findings reveal an essential oncogenic role of BMAL2 and demonstrate that it is an appealing therapeutic target, especially for ARID1A-wt OCCC.
Costa DG, Gee LM, Lee G
… +17 more, Sales Gomez L, Franco AC, Vizioli MG, Valdivieso K, Zhang LJ, Pirius N, Martini H, Porritt RA, Saul D, Cavadas C, Ebert S, LeBrasseur NK, Khosla S, Passos JF, Adams CM, Robbins PD, Jurk D
EMBO Mol Med
· 2026 May · PMID 41922652
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Cellular senescence drives aging and age-related dysfunction across multiple tissues, including the brain. Through a high-content, senescent cell-based phenotypic screen of a small panel of natural products, we identifie...Cellular senescence drives aging and age-related dysfunction across multiple tissues, including the brain. Through a high-content, senescent cell-based phenotypic screen of a small panel of natural products, we identified tomatidine, an aglycone of tomatine found in tomatoes, as a previously unrecognized senotherapeutic agent. In senescent human brain microvascular endothelial cells and fibroblasts, tomatidine selectively suppressed SASP expression without affecting p16 or p21 levels consistent with a senomorphic effect. In aged mice, tomatidine reduced frailty and improved motor coordination and cognitive performance. These functional benefits were accompanied by reduced senescence markers (p16 , p21 , and telomere-associated DNA damage foci) in liver, skin, and hippocampal neurons, along with decreased neuroinflammation and microglial activation. Tomatidine also diminished brain endothelial cell senescence while enhancing tight junction protein expression, suggesting preserved blood-brain barrier integrity. Together, these findings identify tomatidine as a promising senescence-targeting compound with beneficial effects in aged mice and support its further evaluation in mechanistic and translational studies.
Mayet A, Parma B, Lécuyer D
… +13 more, Defruit A, Rana S, Bodac A, Demetter P, Denanglaire S, Ireland AS, Brandão M, Berghmans T, Andris F, Goriely S, Perentes JY, Oliver TG, Meylan E
EMBO Mol Med
· 2026 May · PMID 41917327
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Tumor-associated neutrophils (TANs) represent a large fraction of immune cells in tumors, but how their regulation and function vary in distinct cancer subtypes remains unknown. In Kras; p53 mouse models of lung adenocar...Tumor-associated neutrophils (TANs) represent a large fraction of immune cells in tumors, but how their regulation and function vary in distinct cancer subtypes remains unknown. In Kras; p53 mouse models of lung adenocarcinoma (LUAD), TANs have an increased lifespan compared to normal neutrophils. Specifically, TANs upregulate the anti-apoptotic protein Bcl-xL, whose blockade by a BH3 mimetic selectively kills ageing TANs and diminishes tumor growth. Here, we have addressed this issue in lung squamous cell carcinoma (LUSC) using the Rosa26; Nkx2-1; Lkb1 mouse model, where we demonstrate increased TAN survival with a rise in Bcl-xL similarly to LUAD. However, unlike in LUAD, inhibiting Bcl-xL alone was insufficient to alter tumor progression in LUSC. After carboplatin and paclitaxel treatment, a combination chemotherapy used in human LUSC, we detected increased neutrophils in circulation, spleen and tumors, and increased Bcl-xL in neutrophils and TANs. Bcl-xL blockade decreased the pool of Bcl-xL-high TANs and synergized with chemotherapy. Altogether, our results suggest distinct outcomes for targeting TANs in different tumor types and reinforce the concept of repurposing BH3 mimetics against cancer.
Alizoti E, Ewald L, Parretta S
… +7 more, March JJK, Meyer-Jens M, Orthey E, Conze C, Carrier L, Robbins J, Singh SR
EMBO Mol Med
· 2026 May · PMID 41917326
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Misfolded proteins cause or contribute to a wide range of progressive diseases that are difficult to treat. Desmin-related (cardio-)myopathy (DRM), a well-studied proteinopathy, presents with progressive muscle weakness...Misfolded proteins cause or contribute to a wide range of progressive diseases that are difficult to treat. Desmin-related (cardio-)myopathy (DRM), a well-studied proteinopathy, presents with progressive muscle weakness and shortened life span. Most DRM patients display intracellular accumulation of desmin and its chaperone αB-crystallin (CRYAB). Using an unbiased high-throughput screen, we found that Janus kinase 1 (JAK1) knockdown resulted in lower CRYAB aggregates in cardiomyocytes. Here, we tested whether the JAK1/2 inhibitor ruxolitinib ameliorates the disease phenotype in CRYAB DRM models. Ruxolitinib cleared pre-existing CRYAB aggregates in neonatal rat cardiomyocytes and human induced-pluripotent stem cell-derived cardiomyocytes, and enhanced ubiquitin-proteasome system (UPS)-mediated degradation. Blocking UPS function and specifically knockdown of the E3 ligase ASB2 blunted the effect of ruxolitinib on CRYAB accumulation. In DRM mice, phospho-STAT3 and JAK1 levels were higher than in non-transgenic mice, indicating pathologically active JAK-STAT signaling. Ruxolitinib treatment resulted in lower CRYAB aggregate load and prevented cardiac dysfunction in DRM mice. Similar findings were obtained by crossing DRM mice with the cardiomyocyte-specific Jak1 knockout, suggesting JAK1 as a therapeutic target in proteinopathy.
Loustau T, Mitrentsi I, Wang N
… +28 more, Spenlé C, Pavlidaki A, Tranchant T, Riegel G, Venu A, Oueidat R, Koch M, Dumas M, Wack F, Hirschler A, Carapito C, Paul N, Carapito R, Mörgelin M, Hansen U, Azzi J, Aubergeon L, Salomé N, Dhaouadi S, Grenot P, Bouhaouala-Zahar B, La Cioppa S, Oertle P, Izzi V, Plodinec M, Noel G, Burckel H, Orend G
EMBO Mol Med
· 2026 May · PMID 41917325
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Given that head and neck squamous cell carcinoma (HNSCC) patients have poor survival outcomes, a better understanding of the therapeutic benefits of ionizing irradiation (IR), the major treatment modality besides surgery...Given that head and neck squamous cell carcinoma (HNSCC) patients have poor survival outcomes, a better understanding of the therapeutic benefits of ionizing irradiation (IR), the major treatment modality besides surgery, is needed. A confounding factor is the immunosuppressive tumor microenvironment determined by tenascin-C (TNC), a highly abundant extracellular matrix molecule upregulated by IR. We investigated the roles of TNC on radio-induced tumor regression in a murine oral HNSCC model expressing or lacking TNC. While tumors in a TNC-expressing host were radiosensitive, they were radioresistant in TNC genetically depleted mice. We identified fibroblast reticular cells (FRCs) as critical regulators. TNC plays a compartmentalized and dual role in regulating tumor radiosensitivity with a detrimental role in the tumor stroma opposed to an essential role in the tumor-draining lymph nodes. This is relevant as a high FRC signature and high TNC levels together correlate with shorter HNSCC patient survival. TNC-expressing FRCs may be an excellent novel target to improve radiotherapy-induced tumor eradication, as our TNC targeting MAREMO peptide reduced tumor cell numbers and plasticity upon IR.
Zhao J, Wang Z, Xiao M
… +10 more, Zhang Y, Liu B, Chen S, Tian Y, Lv D, Wang P, Song H, Wu Y, Liu J, Wang K
EMBO Mol Med
· 2026 May · PMID 41912871
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Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC,...Lung cancer is the leading cause of cancer-related mortality worldwide, with lung squamous cell carcinoma (LUSC) comprising 20-30% of cases. Immunochemotherapy (IC) is the standard first-line treatment for advanced LUSC, yet reliable predictors of therapeutic response remain unavailable. Using single-cell multi-omics profiling of paired pre- and post-treatment tumor and blood samples, we observed that patients responding to IC exhibited significantly higher baseline levels of peripheral blood monocytes, tumor-infiltrating classical monocytes, and APOBEC3A+ monocytes across both compartments compared with non-responders. These associations were independently validated in additional cohorts using routine complete blood count testing and multiplex immunofluorescence analysis of native tumor tissues. Our findings reveal monocyte-related parameters as clinically accessible indicators that link systemic immunity with the tumor microenvironment and hold promise for predicting IC responsiveness in patients with LUSC.
Shostak K, Chen Y, Maurizy C
… +22 more, Rademaker G, Xu X, Blomme A, Close P, Renson O, Van Hul M, Cani PD, Klein S, Florin A, Büttner R, Cataldo D, Delvenne P, Nemazanyy I, Wathieu C, Hego A, Ormenese S, Peulen O, Thiry M, Krishnankutty R, Marques J, von Kriegsheim A, Chariot A
EMBO Mol Med
· 2026 May · PMID 41912870
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The role of phosphatidylcholine transporters such as Stard7 in intestinal cancer development is unknown. To explore this issue, we generated a mouse model lacking Stard7 in intestinal epithelial cells (IECs). Loss of Sta...The role of phosphatidylcholine transporters such as Stard7 in intestinal cancer development is unknown. To explore this issue, we generated a mouse model lacking Stard7 in intestinal epithelial cells (IECs). Loss of Stard7 impaired mitochondrial Complex I activity, led to a severe metabolic and lipid reprogramming, enhanced mitochondrial ROS production and potentiated an mTORC1/ATF4 signature. As a result, levels of enzymes involved in serine biosynthesis were enhanced in Stard7-deficient IECs. We next assessed the consequences of Stard7 deficiency in both Wnt-dependent tumor initiation and in inflammation-driven tumor development. Strikingly, despite generating similar molecular signatures, Stard7 deficiency inhibited tumor development in Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-treated mice but promoted Wnt-driven cancer initiation in the intestine. Apc mice lacking Stard7 in IECs developed more tumors in the distal colon as well as a specific microbiota signature. Collectively, our results suggest that the genetic status critically controls the effects of Stard7 deficiency on intestinal tumor development.
Lier S, Markusson SB, Kocijancic A
… +27 more, Narum M, Lund SO, Böllering B, Lipsa A, Søegaard MLC, Rein ID, Santha P, Jain P, Lång A, Lång E, Meyer N, Dutta A, Anand S, Badugu SB, Nesse GJ, Forstrøm RJ, Klungland A, Anand A, Pollard SM, Bøe SO, Rinholm JE, Frauenknecht KBM, Golebiewska A, Niclou SP, Somyajit K, Lerdrup M, Pandey DP
EMBO Mol Med
· 2026 May · PMID 41882177
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Glioblastomas are the most prevalent and aggressive malignant brain tumors, characterized by hypertranscription and dependence on neurodevelopmental transcription factors. The transcriptional cycle is regulated by phosph...Glioblastomas are the most prevalent and aggressive malignant brain tumors, characterized by hypertranscription and dependence on neurodevelopmental transcription factors. The transcriptional cycle is regulated by phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (RNAPII) by transcriptional cyclin-dependent kinases (tCDKs), including CDK7, CDK9, CDK12, and CDK13. Here we find that glioblastoma stem cells (GSCs) are selectively sensitive to CDK12/CDK13 inhibition, whereas CDK7 and CDK9 inhibition cause non-specific cytotoxicity. This selective targeting halts GSC and organoid proliferation, curtails GSC invasion and suppresses tumor growth in a xenograft mouse model. In GSCs, CDK12/CDK13 inhibition leads to a rapid and genome-wide loss of serine-2 phosphorylation (pSer2) of the RNAPII CTD, abolishing transcriptional elongation and a transcriptional program sustained by key neurodevelopmental transcription factors. CDK12/CDK13 inhibition unexpectedly arrests DNA replication and replication fork progression in a manner distinct from the effect of inhibiting other tCDKs. This dramatic arrest precedes DNA damage response activation and cell cycle arrest, directly linking RNAPII elongation to replication fork dynamics and revealing a previously unrecognized dependence of DNA replication on CDK12/CDK13-RNAPII regulation.
Agbogan VA, Bugault F, Guenin-Macé L
… +12 more, Gribonika I, Planchais C, Morel JD, Delaleu J, Pérez-Chaparro PJ, Atlan M, Delage M, Nassif A, Mouquet H, Belkaid Y, Join-Lambert O, Demangel C
EMBO Mol Med
· 2026 May · PMID 41876796
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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a polybacterial dysbiosis devoid of a known pathogen. Here, we report that HS patients mount IgA and IgG responses against skin coloniz...Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a polybacterial dysbiosis devoid of a known pathogen. Here, we report that HS patients mount IgA and IgG responses against skin colonizers, notably Porphyromonas uenonis (Pu), a rare species selectively enriched in severe disease. In these patients, Pu foci are detected in the epidermis, surrounded by IgA deposits, and anti-Pu IgGs cross-react with self-antigens expressed by healthy keratinocytes. Using healthy human skin explants, we demonstrate that patient-derived Pu can cross an intact epidermal barrier, infect and persist within keratinocytes, triggering their expression of pro-inflammatory mediators. In contrast, topical application of Pu on immunocompetent mice elicit cutaneous and systemic humoral immune responses without tissue infection. These findings uncover an impaired innate immune control of Pu in HS patients, linking keratinocyte infection to skin inflammation and humoral autoimmunity. They underscore the potential of targeting cutaneous dysbiosis as a strategy to limit HS progression.
Singh S, Goel I, Rana A
… +11 more, Gul A, Quadri JA, Mridha AR, Malhotra L, Kashyap N, Radha B, Nayek A, Ajmeriya S, Prasad J, Dhar R, Karmakar S
EMBO Mol Med
· 2026 May · PMID 41876795
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Air particulate matter (PM2.5 and PM10), can cross the placental barrier, triggering oxidative stress and inflammation that compromise fetal development. These insults lead to placental dysfunction and complications incl...Air particulate matter (PM2.5 and PM10), can cross the placental barrier, triggering oxidative stress and inflammation that compromise fetal development. These insults lead to placental dysfunction and complications including preterm birth, low birth weight, and preeclampsia. In cell line and placental explant models, urban particulate matter (UPM) increased pro-inflammatory cytokines and oxidative stress pathways, impairing trophoblast invasion, angiogenesis, and nutrient transport, while also altering epigenetic modifications and endoplasmic reticulum function. Rodent studies revealed reduced litter size, placental abnormalities, and fetal growth arrest along with postnatal neurodevelopmental alterations. Human cohorts from high-exposure regions showed elevated low birth weight rates. Proteomic and transcriptomic analyses of rat placenta revealed an inflammatory signature and altered metabolic networks, while gut microbiome dysbiosis suggested links to metabolic disturbances. Importantly, transcriptomic analysis identified IGFBP3 as a major downregulated gene following UPM exposure. IGFBP3, a key regulator of IGF bioavailability, was suppressed by IL1β, establishing inflammation-driven repression as the mechanism. These findings underscore UPM's multidimensional impact on maternal-fetal health and highlight preventive strategies as urgent priorities.
Chen X, Zhao Y, Xie Y
… +5 more, Liu T, Wang H, Wang X, Guo X, You F
EMBO Mol Med
· 2026 May · PMID 41872511
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Broad-spectrum host-directed antivirals are urgently needed, as virus-targeted drugs often suffer from narrow specificity and rapid resistance. Here, we reported that Betrixaban (BT), an FDA-approved oral Factor Xa inhib...Broad-spectrum host-directed antivirals are urgently needed, as virus-targeted drugs often suffer from narrow specificity and rapid resistance. Here, we reported that Betrixaban (BT), an FDA-approved oral Factor Xa inhibitor, induced a robust antiviral state through dual innate immune pathways. Mechanistically, we identified BT as the first small molecule to directly bind and activate the DNA sensor cGAS to induce cGAMP production. Concurrently, BT inhibited histone deacetylases (HDACs), leading to chromatin de-repression of endogenous retroviruses (ERVs) and production of immunostimulatory double-stranded RNA (dsRNA) that engaged RIG-I/MDA5. These combined signal cascades triggered strong type I interferon responses and conferred broad-spectrum antiviral protection against RNA and DNA viruses in vitro and in vivo. These findings unveil a unique host-directed antiviral strategy wherein a small-molecule drug engages dual nucleic acid-sensing pathway, and suggest repurposing BT as an orally broad-spectrum antiviral.
Kim S, Kim H, Pelayo JP
… +26 more, Alvarez S, Jang G, Kim J, Kim B, Hoelscher VM, Calleja-Pérez B, Jung H, Yang Y, Lee HJ, Lee J, Kim S, de la Peña MJ, Lee Y, Kim S, Han AR, Lee DS, Ji S, Yu W, Kim HM, An JY, Oh WC, Kwon SK, Kim JY, Um JW, Fernández-Jaén A, Ko J
EMBO Mol Med
· 2026 Apr · PMID 41862769
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MDGA1 reportedly suppresses GABAergic synaptic inhibition and may be associated with schizophrenia. However, it has been unclear whether and how MDGA1 dysfunction causes neurodevelopmental disorders. Here, we describe tw...MDGA1 reportedly suppresses GABAergic synaptic inhibition and may be associated with schizophrenia. However, it has been unclear whether and how MDGA1 dysfunction causes neurodevelopmental disorders. Here, we describe two patients with autism spectrum disorder (ASD) carrying missense mutations in MDGA1: p.Val116Met/p.Ala688Val and p.Tyr635Cys/p.Glu756Gln. Murine in utero overexpression of MDGA1 p.Val116Met/p.Ala688Val alters normal cortical neuron migration and impairs ultrasonic vocalizations (USVs). The p.Tyr635Cys/p.Glu756Gln substitution disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in hippocampal CA1 neurons. Male Mdga1 knock-in (KI) mouse pups and adults harboring the p.Tyr636Cys/p.Glu751Gln mutation exhibit impaired USVs and sensorimotor gating, similar to male Mdga1 conditional knockout (cKO) mice. No behavioral deficits were seen in female counterparts. Bazedoxifene (a selective estrogen receptor modulator) treatment of male Mdga1 KI mice rescues the changes in the expression and phosphorylation of a subset of GABAergic synaptic proteins, as well as behavioral performance and GABAergic synaptic strength. Thus, different MDGA1 mutations manifest as distinct MDGA1 dysfunctions and are likely to cause ASD via sexually dimorphic loss-of-function and/or gain-of-function mechanisms.
Llovera G, Heindl S, Varga DP
… +10 more, Lenart N, Kallabis S, Göb V, Stegner D, Escaig R, Nicolai L, Franzmeier N, Meissner F, Denes A, Liesz A
EMBO Mol Med
· 2026 Apr · PMID 41862768
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Our research presents a new animal model of transient ischemic attack (TIA) that mimics brief episodes without cell loss, but results in neuronal and behavioral deficits. We identified excessive microglial reactivity, dr...Our research presents a new animal model of transient ischemic attack (TIA) that mimics brief episodes without cell loss, but results in neuronal and behavioral deficits. We identified excessive microglial reactivity, driven by acute ATP release, as a key factor in post-TIA neurological deficits, which were ameliorated by inhibiting the P2Y12 receptor, a microglia-specific purinergic receptor in the brain parenchyma responsible for activity-dependent microglial cell-cell interactions. This finding suggests that modulation of microglial reactivity offers a promising strategy to prevent cognitive impairment in TIA patients, opening avenues for future research in this underexplored area.
EMBO Mol Med
· 2026 Apr · PMID 41862767
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Transient ischemia attack (TIA) is a brief episode of neurological dysfunction caused by a transient but reversible disruption of blood supply to a specific region of brain without demonstrated tissue injury. Although TI...Transient ischemia attack (TIA) is a brief episode of neurological dysfunction caused by a transient but reversible disruption of blood supply to a specific region of brain without demonstrated tissue injury. Although TIA has long been regarded as a benign cerebral ischemia event, it in fact represents a critical warning for patients and their caregivers, as approximately 23% of patients with ischemic stroke experience TIA hours to days before the onset of acute cerebral infarction (Rothwell and Warlow, 2005). In addition, TIA is associated with long-term cognitive decline, which is a higher risk of dementia (Del Bene et al, 2025). Therefore, timely recognition and management of TIA are essential and more valuable to prevent subsequent stroke and reduce the risk of disability.
Lacourrège M, Jarrosson L, Costechareyre C
… +11 more, Marcel M, Prunet A, Mongellaz M, Futelot C, Rouhani C, Nguyen HG, Aparicio T, Le Bourhis L, Delloye-Bourgeois C, Teinturier R, Castellani V
EMBO Mol Med
· 2026 Apr · PMID 41857452
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Re-arming the immune system to fight cancer holds significant promise. However, models enabling the rapid and reliable evaluation of immunotherapies on patient tumors are still lacking. Here, we report a humanized versio...Re-arming the immune system to fight cancer holds significant promise. However, models enabling the rapid and reliable evaluation of immunotherapies on patient tumors are still lacking. Here, we report a humanized version of the avian model for cell and patient-derived xenograft models, which involves the creation of miniature replicas of patient and cell line-derived tumors in avian embryo tissues. Leveraging this unique technology, we developed two approaches: co-micro-implantation of human PBMCs and cancer cells or implantation of cancer cells followed by the intravenous injection of human PBMCs. By combining whole-embryo light sheet microscopy, analysis of immune cell molecular markers and evaluation of anti-PD-1 therapy in solid tumor models, we demonstrate that the humanized AVI technology recapitulates an immune microenvironment, enables the rapid screening of immune-based therapeutic strategies and supports patient response stratification for biomarker discovery.