Short-chain fatty acids (SCFA) protect against central nervous system (CNS) autoimmunity, but the receptor-mediated mechanisms underlying these effects remain poorly understood, limiting their therapeutic exploitation. Here, we show that selective oral activation of free fatty acid receptor 2 (FFAR2) with the synthetic agonist Cpd1 effectively ameliorates established experimental autoimmune encephalomyelitis (EAE), demonstrating therapeutic efficacy after the onset of the autoimmune response. Cpd1 treatment promoted regulatory T cells and type 3 innate lymphoid cells in the intestine while reducing inflammatory infiltration in the CNS, indicating that modulation of intestinal immunity is sufficient to restrain neuroinflammation. Transcriptomic analysis of intestinal CD4⁺ T cells revealed broad suppression of pathways controlling T-cell activation and proliferation. Mechanistically, the therapeutic effects of Cpd1 required interleukin-22 (IL-22), as antibody-mediated IL-22 neutralization abolished disease protection, identifying IL-22 as a key downstream effector of FFAR2 signaling. Together, these findings establish selective FFAR2 agonism as a tractable strategy to therapeutically modulate the gut-CNS immune axis and identify FFAR2 as a promising target for the treatment of multiple sclerosis and other autoimmune diseases. Free Fatty Acid Receptor 2 (FFAR2) is a receptor for short chain fatty acids, and is expressed on immune cells, including T cells and innate lymphoid cells (ILC). Specific agonism of FFAR2 by oral administration of a synthetic compound Cpd1 is effective in the treatment of experimental autoimmune encephalomyelitis (EAE), delineating a new target for the modulation of CNS autoimmunity. Free Fatty Acid Receptor 2 (FFAR2) is a receptor for short chain fatty acids, and is expressed on immune cells, including T cells and innate lymphoid cells (ILC). Specific agonism of FFAR2 by oral administration of a synthetic compound Cpd1 is effective in the treatment of experimental autoimmune encephalomyelitis (EAE), delineating a new target for the modulation of CNS autoimmunity.
Despite decades of intensive research and substantial clinical gains, malaria remains a major global health challenge exacerbated by the continued emergence of drug-resistant strains of the causative agent, Plasmodium parasites. Encouragingly, recent advances in functional genomics, chemical biology and computational science are reshaping antimalarial drug discovery. In this review, we examine the discovery and development of next-generation antimalarials, including advances in phenotypic and target-based screening, omics-enabled target discovery and emerging therapeutic modalities such as long-acting agents, targeted covalent inhibitors and host-directed therapies. We further evaluate the opportunities and limitations of drug repurposing and discuss how artificial intelligence and data-driven approaches are reshaping target identification, compound optimisation and clinical development. Finally, we argue that future success will depend not only on scientific innovation but also on interdisciplinary collaboration, equitable partnerships, open science and the development of accessible therapies tailored to malaria-endemic populations. In this review, Kelly Chibale, John Woodland, Kathryn J. Wicht and colleagues discuss how functional genomics, chemical biology, artificial intelligence, and emerging therapeutic modalities are transforming antimalarial drug discovery and outline the scientific and collaborative strategies needed to deliver the next generation of accessible malaria therapies.
Respiratory syncytial virus (RSV) remains a major cause of severe respiratory disease, and stabilization of the prefusion (preF) conformation of the F glycoprotein is central for vaccine development. Here, we report a structure-guided engineering strategy that enhances preF stability by reducing the hydrophobic cavity within the trimeric F protein. Targeted modifications at metastability-associated sites generated RVF-88, a disulfide-free stabilized preF immunogen that preserves key neutralizing epitopes, including antigenic site Ø, while exhibiting improved structural integrity and long-term storage stability. Formulated as an unadjuvanted bivalent vaccine, RVF-88 elicited potent neutralizing antibody responses and durable immune protection lasting up to 5 months in mice. Vaccination also protected both mice and cotton rats against RSV challenge. Structural analyses confirmed the intended cavity-reduction design, revealing a reduced apical hydrophobic cavity volume and surface area while maintaining the prefusion architecture. Together, these findings establish hydrophobic cavity reduction as a rational strategy for stabilizing prefusion RSV F and provide a promising next-generation vaccine candidate with improved stability and immunogenicity for further clinical development. A region-prioritized structural optimization strategy enabled development of a low-mutation, disulfide-free RSV prefusion F immunogen with preserved antigenicity and protective activity in vivo. A region-prioritized structural optimization strategy enabled development of a low-mutation, disulfide-free RSV prefusion F immunogen with preserved antigenicity and protective activity in vivo.
Triple-negative breast cancer (TNBC) has a high incidence of metastasis and limited therapeutic options. Here, we identify a multimodal and targetable miR-342-E2F network that regulates metastatic outgrowth in TNBC. Through integrating clinical and experimental datasets, we uncover miR-342 as a suppressor of TNBC metastasis. Temporal re-expression of miR-342 significantly inhibited metastatic progression in both immunocompetent and xenograft TNBC models by specifically limiting the outgrowth of disseminated tumour cells. Using multi-omics profiling, we identified the global complement of miR-342 targets, demonstrating that it directly suppresses transcriptional and post-transcriptional networks that converge to dampen E2F signalling. Single-cell analysis of matched primary and metastatic patient-derived TNBC samples reveals activation of E2F signalling in metastasis that corresponds with reduced miR-342 host gene EVL expression. Furthermore, pharmacologic inhibition of this pathway with the CDK4/6 inhibitor palbociclib specifically reduces metastatic outgrowth of pre-established TNBC lesions. Our findings reveal that TNBCs with low miR-342/high E2F signalling have increased metastatic competency and may be amenable to CDK4/6 inhibitor therapy, offering a potential strategy for targeted intervention to limit TNBC metastasis. Triple negative breast cancers (TNBC) exhibit high rates of metastasis and have few treatment options. As TNBC are heterogeneous, subgroups may be vulnerable to specific treatments. We identify a miR-342-E2F network that regulates metastatic outgrowth of TNBC and is targetable by CDK4/6 inhibition. Triple negative breast cancers (TNBC) exhibit high rates of metastasis and have few treatment options. As TNBC are heterogeneous, subgroups may be vulnerable to specific treatments. We identify a miR-342-E2F network that regulates metastatic outgrowth of TNBC and is targetable by CDK4/6 inhibition.
PRMT5 is expressed at high levels in many cancers, where it regulates diverse cellular pathways that contribute to oncogenesis. Here, we have defined a new role for PRMT5 in regulating and coordinating the interplay between the innate and adaptive immune response. This occurs, in part, through the influence of PRMT5 and E2F1 on RNA splicing and the presence of retained introns (RIs). We found that RIs have a propensity to form double-stranded RNAs that contribute to the innate response. Furthermore, many RIs contain non-canonical open-reading frames (ncORFs), which can be translated and then processed into small peptides that assemble with the MHC class I complex. Significantly, RI-derived peptides are highly immunogenic and, as a murine cancer vaccine, carrying a string of antigenic RI peptides, delayed tumour growth and enhanced survival. RIs are present in human tumour cells, and we identified T lymphocytes in human cancer patients, with antigen specificity for RI-derived peptides, that killed human tumour cells in vitro. Regulating intron retention thus offers a new therapeutic approach to enhance tumour immunogenicity. PRMT5-regulated intron retention generates non-canonical MHC class I antigens that drive anti-tumour immunity and can be exploited for cancer vaccine development. PRMT5-regulated intron retention generates non-canonical MHC class I antigens that drive anti-tumour immunity and can be exploited for cancer vaccine development.
Although diabetic complications are well-established in multiple organs, their impact on the respiratory system remains unclear. Clinical evidence indicates accelerated chronic obstructive pulmonary disease (COPD) progression in individuals with diabetes, yet the underlying mechanisms are poorly defined. Using single-cell RNA sequencing of airway epithelium, we identified distinct transcriptional alterations in COPD patients with or without diabetes, particularly in host–defense pathways related to viral infection, which is a key driver of COPD exacerbations. Functionally, hyperglycemia enhanced influenza virus susceptibility in both COPD-derived epithelial cells and COPD mice with diabetes, indicating compromised airway defense. We further demonstrated that hyperglycemia promotes advanced glycation end products (AGEs) accumulation in airway epithelium, with AGEs levels correlating with infection severity. Pharmacological inhibition of AGEs formation with aminoguanidine significantly reduced viral load both in vitro and in vivo. Mechanistically, AGEs activate p38/ERK/IKK proinflammatory signaling via RAGE and MD2 receptors, leading to epithelial injury and heightened viral susceptibility. Our findings reveal a hyperglycemia-AGEs-RAGE/MD2 axis that increases viral susceptibility in COPD, highlighting AGEs targeting as a promising therapeutic strategy for COPD patients with diabetes. Diabetes worsens COPD by promoting airway epithelial accumulation of advanced glycation end products (AGEs), which increase viral susceptibility via RAGE/MD2-dependent pro-inflammatory signaling. Diabetes worsens COPD by promoting airway epithelial accumulation of advanced glycation end products (AGEs), which increase viral susceptibility via RAGE/MD2‑dependent pro‑inflammatory signaling.
Diabetes is much more than high blood sugar. In this issue of EMBO metabolism, Chen et al (REF Chen et al 2026) show that hyperglycemia impairs the lung’s antiviral defense while driving excessive inflammation through the accumulation of harmful advanced glycation end products (AGEs). As viral infections are a major trigger of chronic obstructive pulmonary disease (COPD) exacerbations and can also worsen glycemic control, these findings provide a mechanistic explanation for the vicious cycle linking diabetes and COPD. By identifying AGEs as key mediators of impaired antiviral immunity, the study highlights AGE inhibition as a promising therapeutic strategy to reduce viral susceptibility and improve outcomes in patients with COPD - diabetes comorbidity. K. Maedler and A. Kruf discuss the study by Chen et al in this issue of EMBO Mol Med, which shows that hyperglycemia impairs antiviral defense in the lung while promoting excessive inflammation through the accumulation of advanced glycation end products (AGEs).
Population proteomics is emerging as a new framework for equitable precision medicine. By studying protein variation across populations, this field bridges population genomics and conventional proteomics to capture the functional molecular states through which genetic ancestry, environmental exposures and other contextual factors shape human health. Here, we discuss how recent advances are moving population proteomics beyond biomarker discovery toward equitable clinical translation through cross-population validation, mechanistic multiomics and global research infrastructures. Its ultimate promise is not to classify populations as fixed biological categories, but to make human diversity measurable, interpretable and clinically actionable for equitable precision medicine. This Comment discusses how recent advances are moving population proteomics beyond biomarker discovery toward equitable clinical translation through cross-population validation, mechanistic multiomics and global research infrastructures.
Pancreatic cancer (PC) continues to demand urgent therapeutic innovation given its limited treatment options. Here, through phenotypic screening of a natural product library followed by systematic validation, we identified chrysosplenetin (CHR) as a bioactive compound with anti-PC activity. Transcriptomic profiling and functional analyses demonstrated that CHR induced endoplasmic reticulum (ER) stress, thereby activating the unfolded protein response (UPR) and subsequent apoptosis, while paradoxically triggering a protective autophagy. Genetic or pharmacological inhibition of autophagy potentiated CHR-induced antitumor efficacy. Using an integrated approach including proteomic analysis, bio-layer interferometry, cellular thermal shift assay, and molecular docking, we confirmed TMED3 as a direct target of CHR. Functional studies revealed that disruption of TMED3 expression partially restored ER homeostasis, attenuating CHR-induced UPR activation and apoptosis. Furthermore, CHR combined with standard chemotherapy or autophagy inhibitors exhibited enhanced antitumor activity in preclinical models, providing a basis for future therapeutic exploration of the TMED3–ER stress axis. Together, our findings establish TMED3 as a novel therapeutic target in PC, revealing that disrupting ER proteostasis via TMED3 perturbation represents a potential therapeutic strategy warranting further investigation. Chrysosplenetin (CHR) induces TMED3 aggregation, causing lethal ER stress in pancreatic cancer and identifying TMED3 as a direct target and druggable vulnerability. CHR combined with gemcitabine or autophagy inhibitors enhances antitumor activity in preclinical models. Chrysosplenetin (CHR) induces TMED3 aggregation, causing lethal ER stress in pancreatic cancer and identifying TMED3 as a direct target and druggable vulnerability. CHR combined with gemcitabine or autophagy inhibitors enhances antitumor activity in preclinical models.
Loss-of-function mutations in the smpd1 gene cause acid sphingomyelinase deficiency (ASMD). Early neurodegeneration and lethality characterize its infantile neurovisceral form (type A). While neuronal dysfunction was traditionally considered the primary driver of the pathology, recent evidence suggests that dysmyelination and microgliosis are not merely secondary features. Specifically, myelin debris undermines the protective role of microglia, contributing to neuroinflammation and neuronal death. Herein, we examined central myelin and oligodendrocyte lineage progression in ASM knockout mice. We show that early-onset dysmyelination results from compromised oligodendrocyte maturation driven by aberrant sphingomyelin-mediated signaling. Transcriptomic profiling revealed that mature oligodendrocytes in these mice retain a gene expression signature similar to oligodendrocyte precursor cells, indicating a differentiation arrest. The cell adhesion molecule CD44 remained significantly upregulated in mature ASMko oligodendrocytes. Pharmacological inhibition of CD44 with verbascoside rescued oligodendroglial maturation in primary culture. Verbascoside administration in vivo restored myelin integrity and improved motor behavior. These findings establish that sphingomyelin homeostasis is critical for oligodendrocyte maturation and identify myelin defects as both primary pathological triggers and therapeutic targets for ASMD with neurologic symptoms. This study shows that sphingomyelin-induced impairment of oligodendrocyte (OL) differentiation and myelin alterations are early pathological events in acid sphingomyelinase deficiency (ASMD) and can be ameliorated by pharmacological inhibition of the extracellular matrix receptor CD44. This study shows that sphingomyelin-induced impairment of oligodendrocyte (OL) differentiation and myelin alterations are early pathological events in acid sphingomyelinase deficiency (ASMD) and can be ameliorated by pharmacological inhibition of the extracellular matrix receptor CD44.
Folate metabolites are chemically unstable: spontaneous decomposition releases formaldehyde, a genotoxin in blood stem cells and a human carcinogen. Despite this, folic acid consumption frequently exceeds the Recommended Dietary Allowance and is prescribed at high doses for patients with blood disorders. However, the impact of excess folate on endogenous formaldehyde genotoxicity in vivo has not been studied. We find that excess tetrahydrofolate (THF) treatment of cell lines elevates formaldehyde-DNA adducts and genotoxicity. To test this in vivo, we fed a high-folic acid diet (10-fold above standard) to mice with heightened sensitivity to formaldehyde: detoxification-impaired Adh5-/- mice, and Fanconi anemia DNA repair mutants Fanca-/- and Fancj-/-. In contrast to cell lines, elevated tissue THF was not associated with increased formaldehyde-DNA adducts nor blood stem cell attrition. Finally, in cancer patients, high-dose folic acid therapy elevated plasma folic acid but did not increase formaldehyde-DNA adducts in peripheral blood mononuclear cells. In conclusion, increased folate in vivo does not elevate endogenous formaldehyde genotoxicity in sensitized mouse models or humans. Folates can decompose to release formaldehyde, a genotoxin and a human carcinogen, raising concern over high-dose folic acid supplementation as a source of formaldehyde. Here, excess folic acid intake did not elevate formaldehyde-DNA damage in formaldehyde-sensitized mice or cancer patients. Folates can decompose to release formaldehyde, a genotoxin and a human carcinogen, raising concern over high-dose folic acid supplementation as a source of formaldehyde. Here, excess folic acid intake did not elevate formaldehyde-DNA damage in formaldehyde-sensitized mice or cancer patients.
Focal segmental glomerulosclerosis (FSGS) is a major cause of nephrotic syndrome and progression to end-stage renal disease, yet its molecular pathogenesis remains still incompletely defined. While transcriptional alterations in podocytes have been extensively characterized, the contribution of post-transcriptional regulatory mechanisms is poorly understood. Here, we combined a zebrafish podocyte-specific injury model with glomerulus-resolved transcriptomic profiling to dissect RNA regulatory alterations during FSGS progression. Integrated analyses of bulk RNA sequencing, small RNA profiling, and alternative splicing revealed pronounced, time-dependent remodeling of the glomerular transcriptome. We demonstrate that podocyte injury is associated with loss of key podocyte-specific proteins, activation of inflammatory pathways, remodeling of the extracellular matrix, and altered microRNA expression, such as miR-21 and miR-193. Moreover, we found that alternative splicing influences key podocyte gene expression, affecting genes critical for slit diaphragm integrity, actin cytoskeleton organization, and glomerular basement membrane stability. Isoform analyses identified FSGS-associated isoform switches in SRSF3 and EPB41L5. Importantly, these changes were also evident in glomeruli from FSGS patients, demonstrating that the zebrafish model recapitulates key molecular features of human disease and highlighting alternative splicing as a central regulatory mechanism in FSGS. Post-transcriptional regulations, such as alternative splicing and microRNA dysregulation, are identified as central and underappreciated processes in injured podocytes in focal segmental glomerulosclerosis (FSGS), with disease-associated isoform switches in SRSF3 and EPB41L5. Post-transcriptional regulations, such as alternative splicing and microRNA dysregulation, are identified as central and underappreciated processes in injured podocytes in focal segmental glomerulosclerosis (FSGS), with disease-associated isoform switches in SRSF3 and EPB41L5.
Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy. Yet, no rapid, non-invasive biomarkers are available for diagnosis or screening. Urine represents an ideal analyte matrix due to its accessibility, low invasiveness, longitudinal sampling, and the kidney’s central role in filtration. Here, we integrated proteomic, lipidomic, and metabolomic analyses of urine from ccRCC patients and controls to identify diagnostic biomarkers. Multi-omics profiling revealed urogenital metabolic dysregulation in ccRCC, including increased lipid metabolism, altered mitochondrial respiration signatures, and elevated urinary lipid content. We identified three urinary protein biomarkers: serum amyloid A1 (SAA1), haptoglobin (HP), and lipocalin 15 (LCN15). Using a parallel reaction monitoring mass spectrometry workflow, we developed a rapid and sensitive assay and combined these markers into a diagnostic UrineScore. The UrineScore achieved 0.96 in an area under the receiver operating characteristic curve analysis in the discovery cohort, and 0.95 in an independent validation cohort. Together, these results support the feasibility of multi-omics-guided urinary biomarker discovery and represent a step toward accessible diagnostic platforms for ccRCC. Urine multi-omics profiling of ccRCC patients identifies a three-protein diagnostic signature (HP, SAA1, and LCN15) that forms a composite UrineScore with an AUROC of 96
Telomere dysfunction and the telomeric DNA damage response (tDDR) activation correlate with aging and age-related diseases, including idiopathic pulmonary fibrosis (IPF). However, a causal role for tDDR in IPF pathogenesis has not been determined. IPF patients frequently bear germline mutations in telomerase genes, critically short telomeres, and markers of tDDR and cellular senescence. We previously demonstrated that telomeric antisense-oligonucleotides (tASOs) targeting telomeric non-coding RNAs are selective tDDR inhibitors. Here, we employed late-generation telomerase knockout mice as a genetic model of IPF. Systemic tASOs treatment reduces DDR—including in stem/progenitor cells—inflammation, and lung fibrosis in young, adult, and old mice. Markers of DDR correlate with lung pathology, and tDDR inhibition normalizes molecular and pathological phenotypes, uncoupling telomere lengths from their deleterious consequences. Transcriptomic changes in telomerase knockout mice recapitulate those observed in normal aged mice and in IPF patients, and they are reversed upon tDDR inhibition. These results highlight the pathogenic causative relevance of tDDR activation in IPF pathogenesis and support tASOs as a promising therapeutic strategy for IPF and for telomere biology diseases. Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no curative therapy. Telomere shortening contributes to IPF, but its pathogenic mechanisms remain unclear. Our study demonstrates that telomeric DNA damage response (tDDR) is a causal and targetable driver of lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no curative therapy. Telomere shortening contributes to IPF, but its pathogenic mechanisms remain unclear. Our study demonstrates that telomeric DNA damage response (tDDR) is a causal and targetable driver of lung fibrosis.
Our understanding of a protective humoral immune response to dengue virus (DENV) remains limited. The envelope (E) protein is the main antibody (Ab) target. While anti-fusion loop (FL) epitope monoclonal Abs (mAbs) can induce antibody dependent enhancement (ADE) in vitro, some mAbs targeting quaternary epitopes can cross-neutralize different DENV serotypes. However, the contribution of each Ab subset to disease outcome remains poorly characterized. We defined DENV2 E epitope-specific Abs dynamics and assessed their association with disease outcome in a cohort of hospitalized and subclinical dengue patients during post-primary DENV2 infection. We quantified and isolated anti-E epitope-specific Abs and tested their enhancing and neutralizing capacity. During the critical phase, FL-targeting antibodies were increased in hospitalized patients compared to subclinical cases. Antibodies targeting quaternary epitopes were reduced in severe dengue compared to classical dengue fever patients. Functionally, quaternary epitope-targeting antibodies showed stronger neutralization and cross-neutralization properties, while FL-binding antibodies displayed stronger in vitro enhancement. These findings show that anti-DENV2 E epitope-specific Ab proportions correlate with disease susceptibility and severity, with important implications for novel vaccine design. Antibodies against dengue virus (DENV) can play both a protective and a disease enhancing role via antibody-dependent enhancement. The envelope (E) protein of the virus is the main target of the antibody (Ab) response. The composition, kinetics, and function of antibodies targeting different epitopes on the E protein, and their direct link to disease severity, remain insufficiently defined during natural infection. Antibodies against dengue virus (DENV) can play both a protective and a disease enhancing role via antibody-dependent enhancement. The envelope (E) protein of the virus is the main target of the antibody (Ab) response. The composition, kinetics, and function of antibodies targeting different epitopes on the E protein, and their direct link to disease severity, remain insufficiently defined during natural infection.
Clear cell renal cell carcinoma exhibits striking intra-tumoral heterogeneity at morphological and genetic levels, complicating treatment and contributing to disease progression. CcRCCs with rhabdoid differentiation are highly aggressive tumors characterized by distinct histopathologies. However, the relationship between morphology, underlying molecular alterations, and tumor behavior remains largely unclear. Here, we present Deep Visual Multi-Omics, an approach integrating digital pathology, morphology-guided single-cell isolation, and ultra-sensitive multi-omics profiling to link cell morphologies to their molecular underpinnings. Across five tumors, we profiled 40,000 AI-classified and expert-curated cells. We identified progressive molecular dysregulation across cells with increasing histopathological grade coexisting within heterogeneous tumors as well as distinct molecular alterations associated with aggressive rhabdoid ccRCC cells, including signatures consistent with enhanced FOXM1-driven proliferation, altered cell-matrix interactions, and a putative immunomodulatory phenotype. Notably, rhabdoid cells exhibited elevated expression of IFN-beta, PD-L1, CD38, ITGB2, and integrin signaling, suggesting that they themselves may act as a source of signals influencing the local immune microenvironment. Besides providing new insights into the biology of ccRCC and highlighting avenues for future translational studies, this illustrates the potential of Deep Visual Multi-omics to dissect cancer heterogeneity and characterize high-risk cell populations. Intra-tumor heterogeneity drives tumor progression and therapy resistance. In ccRCC for example, distinct histopathologies coexist and are associated with patient outcome, yet their molecular basis is poorly understood. Deep Visual Multi-Omics links cell morphology to the underlying molecular state. Intra-tumor heterogeneity drives tumor progression and therapy resistance. In ccRCC for example, distinct histopathologies coexist and are associated with patient outcome, yet their molecular basis is poorly understood. Deep Visual Multi-Omics links cell morphology to the underlying molecular state.
Genomic instability is increased in patients with inflammatory bowel disease (IBD), yet whether it contributes directly to disease pathogenesis remains unclear. Here, we identify RADX, a structural antagonist to RAD51 and a key regulator of replication fork stability, as a critical suppressor of intestinal inflammation by limiting innate immune sensing of replication-associated DNA damage. RADX deficiency exacerbates experimental colitis, with macrophages serving as the principal mediators of this phenotype. Mechanistically, RADX competes with the DNA sensor IFI16 for binding to single-stranded DNA (ssDNA). Loss of RADX promotes ssDNA accumulation, triggering IFI16-dependent activation of NF-κB signaling and inflammasome assembly, thereby driving intestinal inflammation. Consistent with these findings, two RADX variants identified in patients with IBD associate with reduced RADX protein expression, increased DNA damage signaling, and elevated IL-1β levels. Pharmacological inhibition of RAD51 with RI-1 alleviated colitis in both wild-type and Radx-deficient mice. Together, these findings establish a mechanistic link between genome instability and intestinal inflammation, identify a RADX-IFI16 checkpoint that restrains pathogenic innate immune activation, and nominate modulation of replication stress as a therapeutic strategy for IBD. Genomic instability is observed in IBD, yet its pathogenic mechanism is unclear. Here, RADX, replication fork protector, is shown to suppress colitis by limiting ssDNA accumulation and IFI16-dependent inflammation, revealing a new therapeutic vulnerability. Genomic instability is observed in IBD, yet its pathogenic mechanism is unclear. Here, RADX, replication fork protector, is shown to suppress colitis by limiting ssDNA accumulation and IFI16-dependent inflammation, revealing a new therapeutic vulnerability.
Endolysosomal abnormalities are particularly detrimental to the nervous system and have been implicated in neuropsychiatric disorders. Key regulators of the lysosomal and endosomal luminal ion homeostasis are CLC chloride/proton exchangers. We report 15 individuals carrying variants in CLCN3, encoding a ubiquitous endosomal 2Cl−/H+ exchanger, and provide updated clinical information for 5 previously reported individuals. Subjects displayed a broad spectrum of neuropsychiatric symptoms, including developmental delay, intellectual disability, and epilepsy. To reveal the pathogenic mechanism, we investigated ClC-3 variants-mediated ion transport and its regulation by the recently discovered inhibitory beta subunit TMEM9. 12/20 missense variants exhibited altered properties and fell into two classes: those affecting the region binding inhibitory TMEM9 carboxy-termini, and those that broaden the voltage range over which ClC-3 conducts ions. Surprisingly, the latter variants also attenuated TMEM9-mediated inhibition. Both classes produced a toxic gain-of-function, as evident from endolysosomal vacuolization by mutant ClC-3/TMEM9 overexpression. Our results expand the genetic and clinical spectrum of CLCN3-related disease, provide a solid basis for genetic counseling, and uncover an unexpected link between gating-associated conformational changes and inhibition by TMEM9. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms. Loss- and gain-of-function variants of the endosomal chloride/proton exchanger ClC-3 are associated with neurodevelopmental disorders. Identification and characterization of novel variants expands the clinical spectrum of CLCN3 disease and provides detailed insights into pathogenic mechanisms.
Histological analysis is essential for understanding disease pathology and the microenvironment, particularly in Alzheimer’s disease (AD), characterized by beta-amyloid (Aβ) plaques that exist as diffuse, fibrillar, and core species, with distinct toxicity levels. However, accurate classification of Aβ plaque types in postmortem brain tissues and profiling of surrounding cells present significant challenges. To address these challenges, we developed “DeepPlaque”, an integrated system featuring “PlaqueNet”, a deep learning model for automated classification of Aβ plaque species from diverse imaging platforms. DeepPlaque includes automated workflows for cellular phenotyping and proteomic profiling through targeted laser microdissection. PlaqueNet achieves expert-level accuracy (AUC > 90
Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, yet effective interventions remain limited. Ketogenic diet (KD) shows behavioral benefits in ASD, but the underlying mechanisms remain unclear. Here, using Shank3B knockout (KO) mice, we found that KD ameliorates social deficits and induces systemic ketosis with marked elevation of β-hydroxybutyrate (BHB) in KO mice. Oral BHB alone recapitulates KD’s prosocial effects, restoring social interaction and neuronal activity in the anterior cingulate cortex (ACC). Mechanistically, we identified HDAC9 as a region- specific epigenetic target upregulated in ACC neurons of Shank3B KO mice and suppressed by BHB. HDAC9 overexpression in ACC neurons induces social and synaptic deficits, while class IIa HDAC inhibition phenocopies BHB effects. BHB also restores dendritic complexity, excitatory transmission, and AMPA receptor expression. These findings uncover a metabolite-driven epigenetic mechanism linking ketogenic metabolism to the rescue of social behavior via the ACC, and identify HDAC9 as a potential therapeutic target for ASD-related social deficits. β-hydroxybutyrate was shown to improve ASD-related social deficits in a Shank3B-deficient ASD mouse model through suppression of HDAC9 in the anterior cingulate cortex. β-hydroxybutyrate was shown to improve ASD-related social deficits in a Shank3B-deficient ASD mouse model through suppression of HDAC9 in the anterior cingulate cortex.
