Joshi AS, Tomaz da Silva M, Vuong AT
… +3 more, Xu B, Singh RK, Kumar A
EMBO Mol Med
· 2025 Dec · PMID 41249735
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Cancer cachexia is a debilitating syndrome characterized by the progressive loss of skeletal muscle mass with or without fat loss. Recent studies have implicated dysregulation of the endoplasmic reticulum (ER) stress-ind...Cancer cachexia is a debilitating syndrome characterized by the progressive loss of skeletal muscle mass with or without fat loss. Recent studies have implicated dysregulation of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways in skeletal muscle under various conditions, including cancer. In this study, we demonstrate that the IRE1α/XBP1 branch of the UPR promotes activation of the ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid metabolism in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Moreover, we show that the IRE1α/XBP1 pathway is a key contributor to muscle wasting. Skeletal muscle-specific deletion of the XBP1 transcription factor significantly attenuates tumor-induced muscle atrophy. Mechanistically, transcriptionally active XBP1 binds to the promoter regions of genes such as Map1lc3b, Fbxo32, and Il6, which encode proteins known to drive muscle proteolysis. Pharmacological inhibition of IRE1α using 4µ8C in KPC tumor-bearing mice attenuates cachexia-associated molecular changes and improves muscle mass and strength. Collectively, our findings suggest that targeting IRE1α/XBP1 pathway may offer a therapeutic strategy to counteract muscle wasting during pancreatic cancer-induced cachexia.
Ballesteros-González I, Hernández-Navas I, Brehey O
… +20 more, Lechuga CG, Salmón M, Scotece M, Velasco-Vicente R, Flores-Gómez AA, Cebriá A, Simón-Carrasco L, Jiménez G, Musteanu M, Guerra C, Domínguez O, Caleiras E, Blanco-Aparicio C, Pons T, Ferrer I, Paz-Ares L, Torres-Ruiz R, Rodríguez-Perales S, Barbacid M, Drosten M
EMBO Mol Med
· 2025 Dec · PMID 41219537
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KRAS mutations are responsible for a quarter of all lung adenocarcinomas. However, the molecular mechanisms linking these mutations and their frequent secondary dosage amplification to tumor formation are still not fully...KRAS mutations are responsible for a quarter of all lung adenocarcinomas. However, the molecular mechanisms linking these mutations and their frequent secondary dosage amplification to tumor formation are still not fully understood. While ample evidence supports a crucial role for the MAPK pathway in tumor development, the primary effectors targeted by this pathway remain largely unexplored. Here we identify the transcriptional repressor Capicua (CIC) as a key target inactivated by KRAS/MAPK signaling in lung adenocarcinoma. We show that genetic loss of CIC recapitulates the phenotypic consequences of amplified KRAS signaling. Genetic disruption of CIC suppressed the requirement for Kras allelic imbalances and accelerated the transformation of bronchiolar Club cells. We also demonstrate that restoring CIC repressor activity impaired proliferation of CIC-deficient tumor cells and reverted resistance to MAPK pathway inhibitors. These results highlight the key role of CIC during lung tumor formation and suggest that selective pressure for effective CIC inactivation favors secondary amplification of KRAS/MAPK signaling in tumor cells.
Sharma Y, Bhatia P, Rangappa G
… +2 more, Saha S, Raghu P
EMBO Mol Med
· 2025 Dec · PMID 41219536
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Coordination of cellular and physiological development by signaling is required for normal brain structure and function. Mutations in OCRL, a phosphatidylinositol 4,5 bisphosphate [PI(4,5)P], 5-phosphatase leads to Lowe...Coordination of cellular and physiological development by signaling is required for normal brain structure and function. Mutations in OCRL, a phosphatidylinositol 4,5 bisphosphate [PI(4,5)P], 5-phosphatase leads to Lowe Syndrome (LS). However, the mechanism by which mutations in OCRL leads to the neurodevelopmental phenotypes of LS is not understood. We find that on differentiation of LS patient iPSC, neural cultures show reduced excitability and enhanced GFAP levels. Multiomic single-nucleus RNA and ATACseq analysis of neural stem cells revealed enhanced numbers of cells with a gliogenic cell state. Analysis of snRNA seq revealed increased levels of DLK1, a Notch ligand in LS patient NSC associated increased levels of cleaved Notch and elevation of its transcriptional target HES5, indicating upregulated Notch signaling. Treatment of iPSC derived brain organoid with an inhibitor of PIP5K, the lipid kinase that synthesizes PI(4,5)P, was able to restore neuronal excitability and rescue Notch signaling defects in OCRL deficient organoids. Overall, our results demonstrate a role for PI(4,5)P dependent regulation of Notch signaling, cell fate specification and neuronal excitability regulated by OCRL.
Li L, Li T, Wang B
… +17 more, Feng J, Zhang N, Zhang J, Niu Z, Li W, Gao H, Wang Q, Liu Y, Chen Y, Zhang Y, Bian Y, Pan T, Sheng S, Li X, Liu J, Yang B, Liang H
EMBO Mol Med
· 2025 Dec · PMID 41214391
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Cardiac hypertrophy is one of the significant causes of heart failure and is closely related to the rising rate of hospitalization and readmissions. Given the diverse regulatory roles of alternative splicing in cardiovas...Cardiac hypertrophy is one of the significant causes of heart failure and is closely related to the rising rate of hospitalization and readmissions. Given the diverse regulatory roles of alternative splicing in cardiovascular diseases, RNA-binding proteins have attracted increasing research attention. Here, for the first time, we discovered elevated expression of RBMS1 in heart tissues of patients with dilated cardiomyopathy and in mice with cardiac hypertrophy. We demonstrated that RBMS1 activated the PI3K/AKT signaling pathway by promoting the splicing CTTN to generate CTTN-Δe11 splicing isoform, resulting in cytoskeleton and sarcomere damage in cardiomyocytes. Additionally, pharmacological inhibition of RBMS1 by nortriptyline alleviated cardiac hypertrophy and heart failure. These results provide a new perspective for developing novel therapeutic approaches for cardiac hypertrophy and establish a theoretical basis for targeting RBMS1 in the clinical treatment of cardiac hypertrophy.
EMBO Mol Med
· 2025 Dec · PMID 41214390
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Cetuximab, an EGFR-targeting monoclonal antibody, provides beneficial yet limited clinical improvement in KRAS wild-type metastatic colorectal cancer (mCRC). While circRNA dysregulation has been implicated in various can...Cetuximab, an EGFR-targeting monoclonal antibody, provides beneficial yet limited clinical improvement in KRAS wild-type metastatic colorectal cancer (mCRC). While circRNA dysregulation has been implicated in various cancers, the role of circ-EGFR in response to EGFR-targeted therapy in mCRC remains largely unexplored. Here, we identified circ-EGFR as a promising predictive biomarker for cetuximab response. Clinically, we first determined that tissue-based circ-EGFR biomarker effectively stratified responders from non-responders to cetuximab in mCRC, with an Area under the Curve (AUC) of 76.8%. Functional assays demonstrated that circ-EGFR enhances the sensitivity to cetuximab, whereas its depletion induces resistance in CRC. Mechanistically, we revealed that circ-EGFR functions as a sponge for miR-942-3p, resulting in the upregulation of GAS1, which activates the Hedgehog signaling pathway and promotes the efficacy of cetuximab in CRC. Importantly, we effectively translated this tissue-based biomarker into a liquid biopsy predictor for anti-EGFR response (AUC: 76.9%), highlighting its non-invasive potential. In conclusion, circ-EGFR is a significant predictor of cetuximab efficacy in mCRC, potentially aiding in patient selection and treatment management, especially for patients with low circ-EGFR expression.
EMBO Mol Med
· 2025 Dec · PMID 41214389
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The introduction of monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) has represented a milestone in the management of metastatic colorectal cancer (mCRC). Cetuximab significantly improves outco...The introduction of monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) has represented a milestone in the management of metastatic colorectal cancer (mCRC). Cetuximab significantly improves outcomes in patients with wild-type tumors, yet only about one third derive durable benefit. This discrepancy underscores the biological heterogeneity of EGFR signaling and the urgent need for biomarkers capable of predicting therapeutic response beyond status.
Karampelias C, Yang K, Farkas FJ
… +10 more, Sterr M, Molina van Den Bosch M, Renner S, Fuß J, von Toerne C, Franzenburg S, Kin T, Wolf E, Kemter E, Lickert H
EMBO Mol Med
· 2025 Dec · PMID 41188536
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Primary human pancreatic ductal organoids (HPDO) have emerged as a model to study pancreas biology and model disease like pancreatitis and pancreatic cancer. Yet, donor material availability, genetic variability and a la...Primary human pancreatic ductal organoids (HPDO) have emerged as a model to study pancreas biology and model disease like pancreatitis and pancreatic cancer. Yet, donor material availability, genetic variability and a lack of extensive benchmarking to healthy and disease pancreas limits the range of applications. To address this gap, we established porcine pancreatic ductal organoids (PPDO) as a system from a reliable, genetically defined and easily obtainable source to model pancreatic ductal/progenitor biology. We benchmarked PPDO to HPDO and primary porcine pancreas using single-cell RNA sequencing (scRNA-Seq). We observed no overt phenotypic differences in PPDO derived from distinct developmental stages using extensive proteomics profiling, with a WNT/basal cell signaling enriched population characterizing PPDO. PPDO exhibited differentiation potential towards mature ductal cells and limited potential towards endocrine lineages. We used PPDO as a chemical screening platform to assess the safety of FDA-approved drugs and showed conserved toxicity of statins and α-adrenergic receptor inhibitors between PPDO and HPDO cultures. Overall, our results highlight the PPDO as a model for mammalian duct/progenitor applications.
Hirschberger S, Müller MB, Mascolo H
… +24 more, Seitz M, Nibler S, Effinger D, Lu K, Büch J, Bender M, Kammerer T, Peterß S, Kleigrewe K, Abele M, Barth T, Kushnir O, Imhof A, Dietzel S, Wegener B, Sowa R, Vogel F, Lamm P, Tomasi R, Unger K, Sperandio M, Kilger E, Kreth S, Hübner M
EMBO Mol Med
· 2025 Dec · PMID 41184637
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Cytotoxic T cell (CTL) dysfunction is a hallmark of immune paralysis after major surgery, increasing susceptibility to severe nosocomial infections and contributing to mortality in critically ill patients. The mechanisms...Cytotoxic T cell (CTL) dysfunction is a hallmark of immune paralysis after major surgery, increasing susceptibility to severe nosocomial infections and contributing to mortality in critically ill patients. The mechanisms remain poorly understood. We demonstrate that reactive oxygen species (ROS) released by myeloid-derived suppressor cells (MDSC) transiently emerging after surgery, drive perioperative CTL immunoparalysis. These ROS damage CTL mitochondria, triggering secondary mitochondrial ROS amplification and overwhelming antioxidant defenses. The resulting oxidative cascade impairs oxidative phosphorylation and suppresses CTL effector function. Concurrently, stress-induced mitochondrial hyperfusion disrupts fission-dependent translocation to the immunological synapse, exacerbating bioenergetic failure. MitoTEMPO, a mitochondria-targeted antioxidant, partially mitigates these effects, highlighting mitochondrial stabilization as a potential strategy to prevent perioperative immune dysfunction.
Molina Panadero I, Moreno Rodríguez A, Rey Hidalgo A
… +11 more, de la Cruz M, Sánchez P, Tomás Gallardo L, Samernate T, Sencanski M, Glisic S, Genilloud O, Nonejuie P, Pérez-Pulido AJ, Hmadcha A, Smani Y
EMBO Mol Med
· 2025 Dec · PMID 41174184
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High-throughput screening studies provide an additional approach to discovering repurposed drugs for antimicrobial treatments. In this work, we report the identification of ENOblock, an anticancer drug, as an antimicrobi...High-throughput screening studies provide an additional approach to discovering repurposed drugs for antimicrobial treatments. In this work, we report the identification of ENOblock, an anticancer drug, as an antimicrobial agent. We computationally and experimentally validated that ENOblock synergizes with colistin, the last resort antibiotic. Additionally, we identified enolase as the potential bacterial target for ENOblock. The in silico and in vitro antibacterial activity of ENOblock translated into potent in vivo efficacy in an animal infection model. Collectively, the preclinical data support the selection of ENOblock as a promising candidate for antimicrobial development, with the potential to address the urgent threat of infections caused by Acinetobacter baumannii.
Lan JL, Chang SH, Lai YH
… +13 more, Li JP, Chen GJ, Lin YJ, Huang YL, Chiang BL, Chang JG, Lu GY, Tsai TL, Lin CY, Wang J, Li YC, Hung MC, Yang CA
EMBO Mol Med
· 2025 Dec · PMID 41168503
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The role of zinc finger protein 334 (ZNF334) in immunological processes remains unknown. We identified a ZNF334 truncation mutation (p.Thr399fs) in a rare case of late-onset cold-induced autoinflammatory disease with ele...The role of zinc finger protein 334 (ZNF334) in immunological processes remains unknown. We identified a ZNF334 truncation mutation (p.Thr399fs) in a rare case of late-onset cold-induced autoinflammatory disease with elevated TNF-α, IL-1β, IL-6, and extracellular heat shock protein 90 (eHsp90) plasma levels and progressive sensorineural hearing loss. Using patient-derived monocytes and CRISPR/Cas9-edited THP-1 monocytes with a ZNF334 truncation mutation, we discovered that the mutation reduced the interaction between ZNF334 and Hsp90, diminished the endogenous levels of the cold stress regulators Hsp90 and transient receptor potential melastatin 8 (TRPM8), disrupted ER protein folding response and redox homeostasis, and increased cold-induced NF-κB activation and secretion of the proinflammatory TRPM8+ mitochondria-containing extracellular vesicles in monocytes. Long-term cold avoidance alleviated the patient's cold-induced symptoms. In addition, treatment of ZNF334-truncated THP-1 cells with an Hsp90 inhibitor prevented cold-induced TNF and NLRP3 upregulations. Our findings suggest ZNF334 as an essential regulator of cold-induced inflammation and oxidative stress, and Hsp90 ATPase inhibitors might be effective in the treatment of autoinflammatory diseases induced by repeated mild cold exposure.
Jiménez-Loygorri JI, Shang P, Bayramoglu I
… +12 more, Gómez-Sintes R, Martín-Segura A, Ambrosino H, Hoang J, Díaz A, Geng Z, Gavathiotis E, Dutton JR, Dengjel J, Cuervo AM, Ferrington DA, Boya P
EMBO Mol Med
· 2025 Dec · PMID 41168502
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Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described i...Autophagy is one of the main intracellular recycling systems and its impairment is considered a primary hallmark of the aging process. Defective macroautophagy in the retinal pigment epithelium (RPE) has been described in age-related macular degeneration (AMD), a blindness-causing disease that affects roughly 200 million patients worldwide. The relevance of chaperone-mediated autophagy (CMA), a selective type of autophagy for proteins containing a KFERQ-like motif, in RPE cell biology and homeostasis remains to be elucidated. Here we describe decreased CMA activity in the RPE of AMD patients compared to healthy age-matched controls, along with accumulation of substrate proteins, and in donor-derived iPSC-RPE cells, which we used to further characterize AMD-associated alterations of cellular homeostasis derived from proteotoxicity. Treatment with CA77.1 (CMA activator) restores proteostasis and remodels specific subsets of the proteome in cells from healthy and AMD donors. CA77.1-treated AMD iPSC-RPE display reduced oxidative stress and improved mitochondrial function. These findings may explain the specific vulnerability of the RPE during AMD and shed light on CMA as a new druggable target for this as-of-now incurable disease.
Zhu J, Huang Y, Li X
… +8 more, Liu B, Yuan L, Wang L, Qian K, Mao Y, Xu Y, Du L, Cheng X
EMBO Mol Med
· 2025 Dec · PMID 41145761
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Early detection of gastric cancer (GC) is critical for improving prognosis, yet conventional biomarkers lack sensitivity and specificity, necessitating non-invasive, high-performance diagnostic tools. This study integrat...Early detection of gastric cancer (GC) is critical for improving prognosis, yet conventional biomarkers lack sensitivity and specificity, necessitating non-invasive, high-performance diagnostic tools. This study integrated untargeted metabolomics and machine learning to develop a plasma metabolite panel for GC diagnosis and mechanistic insights. Plasma and tissue samples from two cohorts (n = 597) were analyzed using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). A six-metabolite panel was identified and validated, demonstrating excellent diagnostic performance (area under the curve: 0.947-0.982 in discovery; 0.920-0.951 in validation) and superior sensitivity (0.900-0.940) compared to conventional markers (0.020-0.240). Isovalerylcarnitine (C5), a key component, was consistently downregulated in both plasma and tissue samples. Mendelian randomization supported a causal relationship between isovalerylcarnitine (C5) and GC risk. Proteomic analyses revealed inverse correlations between C5 and cadherin/MMP family proteins. Functional assays confirmed that isovalerylcarnitine (C5) inhibited GC cell migration and invasion via calpain-mediated cleavage of VE-cadherin and MMP2. This study identifies a robust diagnostic metabolite panel for GC detection and highlights a novel mechanistic role of isovalerylcarnitine (C5) in GC progression, supporting its utility as both a biomarker and therapeutic target.
Jeanpierre M, Debeaupuis O, Brunaud C
… +27 more, Yancoski J, Riller Q, Hadjadj J, Stolzenberg MC, Villarreal G, Katsicas MM, Villa M, Neves JF, Stephan JL, Léonard C, Lazaro E, Ciron J, Boussard C, Mazerolles F, Magerus A, Olivier P, Masson C, Schmitt Y, Hoareau B, Vinit A, Neven B, Quartier P, Isambert H, Oleastro M, Danielian S, Parlato M, Rieux-Laucat F
EMBO Mol Med
· 2025 Dec · PMID 41136770
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Characterization of primary immune dysregulations and deficiency disorders caused by hyperactivating variants of the JAK/STAT pathway highlighted its crucial role in immune cell development and response. To systematicall...Characterization of primary immune dysregulations and deficiency disorders caused by hyperactivating variants of the JAK/STAT pathway highlighted its crucial role in immune cell development and response. To systematically evaluate pathogenic JAK1 variants, we developed a structure-based predictive framework adapting AlphaFold2, modeling both the active and inactive conformations of JAK1. Dual-state modeling of 21,926 JAK1 variants enabled discrimination between pathogenic and benign variants based on their impact on regulatory conformation. Applying this approach to a large cohort of patients with suspected primary immune dysregulation and deficiency led to the identification of five novel variants located in key cis-regulatory and catalytic domains, with predicted gain of function activity. Ectopic expression of these variants in cell line resulted in varying levels of hyperactivation of JAK1 and multiple STATs at baseline. Furthermore, treatment of two patients with Tofacitinib suppressed JAK1 hyperactivation, normalized plasma cytokine levels and interferon signatures, and significantly improved clinical symptoms. These findings reveal diverse mechanisms of JAK1 gain of function, expanding the clinical spectrum JAK1 GOF, and underscore the importance of precise variant characterization for effective personalized therapy.
Aidarova A, Carels M, Haegman M
… +14 more, Driege Y, Timmermans S, Van Damme E, Aguilera-Lizarraga J, Viola MF, de Cássia Collaço R, Manils J, Ley SC, Bosmans F, Van de Wiele T, Boeckxstaens G, Libert C, Beyaert R, Afonina IS
EMBO Mol Med
· 2025 Dec · PMID 41131424
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CARD14 is an intracellular NF-κB signaling mediator in the skin, and rare CARD14 variants have been associated with psoriasis and atopic dermatitis. CARD14 is also expressed in intestinal epithelial cells (IEC). However,...CARD14 is an intracellular NF-κB signaling mediator in the skin, and rare CARD14 variants have been associated with psoriasis and atopic dermatitis. CARD14 is also expressed in intestinal epithelial cells (IEC). However, its function in the intestine remains unknown. We demonstrate here that transgenic mice expressing the psoriasis-associated gain-of-function human CARD14(E138A) mutant specifically in IEC show mild intestinal inflammation, without epithelial damage. Moreover, CARD14(E138A) mice show a drastic reduction in intestinal motility, often associated with rectal prolapse. Enteric neuronal survival and functionality are unaffected in CARD14(E138A) mice. Transcriptome analysis of IEC from CARD14(E138A) mice reveals decreased expression of antimicrobial peptides by Paneth cells, accompanied by microbial dysbiosis and increased susceptibility to enteric bacterial infection. Our findings suggest that gain-of-function CARD14 mutations may not only predispose patients to psoriasis but also mild intestinal inflammation, reduced intestinal motility, and increased sensitivity to intestinal infection. CARD14(E138A) mice are also a valuable tool for further investigation of IEC-intrinsic molecular processes involved in intestinal inflammation and motility disorders.
Parashar S, Oliaeimotlagh M, Roy P
… +8 more, Lyu Q, Bellapu A, Fomin M, Kumar S, Wang Y, McSkimming CC, McNamara CA, Ley K
EMBO Mol Med
· 2025 Dec · PMID 41120678
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Under conditions of chronic unresolved inflammation characteristic of atherosclerosis, regulatory CD4 T cells (Tregs) become unstable and convert to cytotoxic exTregs. The mechanism driving this conversion in humans is u...Under conditions of chronic unresolved inflammation characteristic of atherosclerosis, regulatory CD4 T cells (Tregs) become unstable and convert to cytotoxic exTregs. The mechanism driving this conversion in humans is unclear. Here, we show unresolved endoplasmic reticulum (ER) stress as a key factor driving Treg instability. Human exTregs undergo ER stress and consequent mitochondrial dysfunction that remains unchecked due to defective mitophagy. Integrated stress response (ISR), a pathway that can trigger inflammatory signaling, is also upregulated in exTregs. exTregs are highly apoptotic and are more susceptible to stress-mediated cellular dysfunction due to their senescent state. In a phenotype reminiscent of exTregs, Tregs from coronary artery disease (CAD) patients show high ER stress and mitochondrial depolarization. This is further exacerbated in CD4 T cells residing in atherosclerotic plaques. Pro-atherosclerotic stressors such as oxLDL and interferon-γ induce ER stress and mitochondrial dysfunction in Tregs in vitro. We conclude that the maladaptive inflammatory environment in atherosclerosis triggers ER stress and mitochondrial dysfunction, contributing to Treg instability in CAD.
Long RKM, Korbmacher F, Ronchi P
… +8 more, Fleckenstein H, Schorb M, Mirza W, Mallorquí M, Aguilar R, Moncunill G, Schwab Y, Bernabeu M
EMBO Mol Med
· 2025 Nov · PMID 41102495
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Disruption of the vascular protective angiopoietin-Tie axis is common in cerebral malaria (CM) patients, who display elevated angiopoietin-2 (Ang-2) and reduced angiopoietin-1 (Ang-1) blood concentrations. The role of pe...Disruption of the vascular protective angiopoietin-Tie axis is common in cerebral malaria (CM) patients, who display elevated angiopoietin-2 (Ang-2) and reduced angiopoietin-1 (Ang-1) blood concentrations. The role of pericytes in CM pathogenesis remains unexplored, despite being a major source of brain Ang-1 secretion and evidence of pericyte damage observed in CM postmortem samples. Here, we engineered a human 3D microfluidics-based brain microvessel model containing the minimal cellular components to replicate the angiopoietin-Tie axis, human primary brain microvascular endothelial cells, and pericytes. This model replicated pericyte vessel coverage and ultrastructural interactions present in the brain microvasculature. When exposed to P. falciparum-iRBC egress products, 3D brain microvessels presented decreased Ang-1 secretion, increased vascular permeability, and minor ultrastructural changes in pericyte morphology. Notably, P. falciparum-mediated barrier disruption was partially reversed after pre-treatment with recombinant Ang-1 and the Tie-2 activator, AKB-9778. Our approach suggests a novel mechanistic role of pericytes in CM pathogenesis and highlights the potential of therapeutics that target the angiopoietin-Tie axis to rapidly counteract vascular dysfunction caused by P. falciparum.
Li A, Huang S, Cao SQ
… +20 more, Lin J, Zhao L, Yu F, Huang M, Yang L, Xin J, Wen J, Yan L, Zhang K, Jiang M, Le W, Li P, Liu YU, Qin D, Lu J, Lu G, Shen H, Yao X, Fang EF, Su H
EMBO Mol Med
· 2025 Nov · PMID 41094045
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Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria prov...Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1-Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1-Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.
Schomakers BV, Passadouro AS, Trętowicz MM
… +16 more, Simpson PJ, Jaspers YRJ, van Weeghel M, Hu IM, Lamboo CME, Cloutier D, Byrne BJ, van Klinken JB, Janssen PML, Piersma SR, Jimenez CR, Vaz FM, Salomons GS, van der Velden J, Houtkooper RH, Mosegaard S
EMBO Mol Med
· 2025 Nov · PMID 41083823
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Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of...Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. This study describes a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.
Xiong Y, Zeng F, Luo K
… +7 more, Wang L, Li M, Chen Y, Huang T, Xu C, Xu G, Zou H
EMBO Mol Med
· 2025 Nov · PMID 41083822
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The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangi...The proliferation of glomerular mesangial cells is a fundamental pathological change in immunoglobulin A nephropathy (IgAN). This study aims to elucidate the mechanisms that affect the proliferation of glomerular mesangial cells. Bioinformatics analysis combined with clinical detection identified the key molecule glycine decarboxylase (GLDC). In vitro experiments revealed that GLDC knockdown reduces the proliferative effect of pIgA on mesangial cells. Pyrimidine metabolism is involved in the proliferation regulation of mesangial cells by GLDC. Additionally, GLDC's regulation of glycolysis in mesangial cells was discovered, which further affects the progression of renal fibrosis and the proliferation of glomerular mesangial cells. Upon knockdown of the key rate-limiting enzymes of pyrimidine metabolism, CAD and DHODH, the overexpression of GLDC lost its regulatory effect on glycolysis. The regulatory mechanisms described above were confirmed by inhibiting GLDC expression in the kidneys in vivo. In conclusion, GLDC upregulates pyrimidine metabolic flux, which subsequently fuels glycolysis to promote mesangial cell proliferation, promoting IgAN progression.
Woo MS, Therriault J, Hosseini SA
… +31 more, Wang YT, Macedo AC, Rahmouni N, Aumont É, Servaes S, Tissot C, Fernandez-Arias J, Trudel L, Hall B, Bezgin G, Quispialaya-Socualaya K, Goncalves M, Chan T, Stevenson J, Zheng Y, Mitchell S, Hopewell R, Pola I, Tan K, Di Molfetta G, Lussier FZ, Massarweh G, Vitali P, Soucy JP, Gauthier S, Ashton NJ, Blennow K, Pascoal TA, Zetterberg H, Benedet AL, Rosa-Neto P
EMBO Mol Med
· 2025 Nov · PMID 41073674
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Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD...Accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are followed by the activation of glia cells and infiltration of peripheral immune cells that collectively accelerate neurodegeneration in preclinical AD models. Yet, the role of neuroinflammation for neuronal injury and disease progression in preclinical and early symptomatic AD remains elusive. Here, we combined multiplexed immunoassays and SomaScan proteomics of the cerebrospinal fluid (CSF) with MRI and PET brain imaging of people across the AD continuum to identify pathways that are associated with AD progression. Unbiased clustering revealed that glia-mediated inflammation, activation of cell death pathways (CDPs) and synaptic pathologies were among the earliest Aβ-induced changes, and were associated with disease progression in preclinical AD. Mediation analysis revealed that activation of CDPs were decisive drivers of inflammation in early symptomatic AD. The cycle of glia-mediated neuroinflammation and neuronal injury characterizes preclinical AD and has implications for novel treatment approaches.