RXRα suppression drives hepatic metabolic and immune dysfunction in sepsis - EMBO Molecular Medicine

Sepsis is a life-threatening condition in which a dysregulated host response to infection leads to organ dysfunction and metabolic and immune failure. We identify hepatocyte retinoid X receptor α (RXRα) as a key integrator of host resilience during polymicrobial sepsis. RXRα is transcriptionally regulated by hepatocyte nuclear factor 4α (HNF4α), and sepsis rapidly decreases RXRα mRNA and protein levels. Transcriptomic analyses show that the septic liver becomes partially resistant to pharmacological activation of RXRα with bexarotene. Prophylactic- but not therapeutic- bexarotene improves survival by preserving metabolic stability and enhancing bacterial clearance. In hepatocyte-specific inducible RXRα-deficient mice, this protection is lost, confirming dependence on hepatocyte RXRα. Loss of RXRα in hepatocytes reduces Kupffer cell numbers, resulting in bacterial dissemination and mortality, a phenotype reproduced in a genetic model of selective Kupffer cell ablation. Overall, RXRα maintains the hepatic macrophage niche, linking hepatocellular transcriptional competence to systemic antibacterial defense.

doi.org

Selective mRNA translation determines adaptative mutability of melanoma cells to anti-BRAF/MEK combination therapy - EMBO Molecular Medicine

During their inevitable evolution towards acquired resistance to anti-cancer targeted therapies, cancer cells adopt distinct gene expression profiles that allow them to transiently adapt to and tolerate the treatment. Cancer cells surviving therapy can increase their mutation rate, enhancing the likelihood of acquiring resistance-conferring mutations and evolving into resistant cells. Here we show that translational control mediates the adaptive mutability of melanoma drug-tolerant cells by regulating the translation of the error-prone non-homologous end joining (NHEJ) component 53BP1. The specific inhibition of 5’UTR-driven 53BP1 mRNA translation was sufficient to impair NHEJ and mutability. We found that the eIF4A RNA helicase, regulates 53BP1 mRNA translation. Consequently, targeting the eIF4A with two small molecule inhibitors significantly delays the acquisition of resistance to combination of BRAF and MEK inhibitors in BRAFV600-mutant melanoma xenograft models and cell lines by reducing the mutability of drug-tolerant cells. Our results demonstrate that a standard-of-care therapy for melanoma, by engaging non-genetic adaptation driven at the translational level, contributes to the evolution of drug-tolerant melanoma cells toward acquired resistance.

doi.org

β-hydroxybutyrate restores social deficits by suppressing HDAC9 in the ACC of Shank3B-deficient mice - EMBO Molecular Medicine

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.

doi.org

Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington’s disease - EMBO Molecular Medicine

Huntington’s disease (HD) is a hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by severe neurodegeneration of the basal ganglia and neocortex. No cure is currently available, and new treatment options are urgently needed. Here, we show that the oligomer modifying molecule anle138b (INN: emrusolmin) improves multiple disease phenotypes in cell culture and in two mouse models of HD. Application of anle138b reduced mHTT aggregate formation and ameliorated neurotoxicity in primary neurons. Oral administration of anle138b delayed deposition of mHTT inclusions, reduced brain atrophy, mitigated neuroinflammation and transcriptional alterations, improved motor function and extended life span in HD mice. Downregulation of striatal markers and synapse loss in striatal spiny projection neurons were also partially rescued. No adverse effects of anle138b were observed in wildtype animals. Moreover, anle138b markedly decreased mHTT aggregation in human neural precursor cells differentiated from HD patient-derived induced pluripotent stem cells (iPSCs). Altogether these results illustrate the potential of anle138b as a disease-modifying treatment for HD.

doi.org

Anle138b ameliorates pathological phenotypes in mouse and cellular models of Huntington’s disease - EMBO Molecular Medicine

Huntington’s disease (HD) is a hereditary movement disorder caused by a CAG repeat expansion in the huntingtin gene. HD is characterized by deposition of mutant huntingtin (mHTT) aggregates, and by se...

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The Slr protein of Streptococcus pyogenes is selectively expressed in vivo and is a target for protective antibodies - PubMed

Vaccine candidates are typically identified through characterization of microbial surface antigens expressed under laboratory conditions. Here, we studied the major human pathogen Streptococcus pyogen...

pubmed.ncbi.nlm.nih.gov

Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma - EMBO Molecular Medicine

The unfolded protein response (UPR) is a stress-adaptation pathway and therapeutic target in cancer, yet its pro-survival versus pro-death outcome is difficult to predict because the three ER sensors, PERK, IRE1α, and ATF6, are highly interconnected. Transcriptomic analyses identified sensor-specific gene signatures associated with patient survival across malignancies, and indicated that low IRE1α activity (low XBP1 signature or higher expression of RIDD targets) correlates with improved outcome. We developed SNUPR (single nuclei analysis of the unfolded protein response), an accessible flow cytometry approach that profiles all three branches in nuclear suspensions. SNUPR reveals marked heterogeneity of UPR activation across cancer cell lines that cannot be inferred from sensor expression. This heterogeneity is derived from differences in the strength and duration of PERK-mediated translational inhibition, which gates downstream translation-dependent IRE1α and ATF6 transcriptional programs. Finally, in multiple myeloma, we show that bortezomib-tolerant cells depend on IRE1α activity for survival, linking UPR state to proteasome-inhibitor resistance and positioning SNUPR to guide branch-selective targeting.

doi.org

Hidradenitis suppurativa: skin-colonizing bacteria play an unexpected role

Scientists have revealed that normally harmless Porphyromonas uenonis bacteria play an active role in triggering inflammation and autoimmunity in patients with hidradenitis suppurativa. This discovery...

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Translational bottlenecks in blood-based proteomics - EMBO Molecular Medicine

EMBO Molecular Medicine - The translation of blood-based proteomics into healthcare is no longer constrained primarily by technological limitations, but by unresolved challenges in standardization,...

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Harnessing the glycolysis-TCA cycle axis to boost host defense against neonatal infection - EMBO Molecular Medicine

Preterm infants are highly susceptible to infections that can lead to sepsis, yet therapies beyond antibiotics are limited. Nutrition and host energy metabolism are known as immune modulators, but how they interact to mediate newborn host infection defense remains poorly understood. Here, we identify tricarboxylic acid (TCA) cycle metabolites as key modulators of early life infection outcomes. First, in a birth cohort of 700 children, elevated plasma TCA metabolite levels were associated with reduced infection burdens and systemic inflammation. Next, in a piglet neonatal sepsis model, sustained hepatic TCA cycle activity was associated with survival. These led us to explore clinically relevant nutritional strategies boosting TCA cycle activity. Substituting glucose in parenteral nutrition for galactose or glucogenic amino acids improved both pathogen clearance and preserved glucose homeostasis and prevented lethal sepsis. Mechanistically, these interventions promoted hepatic metabolic rewiring from glycolysis toward TCA-cycle-based oxidative phosphorylation, while mitigating excessive inflammation and organ injury. Our findings establish a clear connection between systemic energy metabolism and neonatal infection defense, suggesting clinically relevant strategies to improve outcomes in vulnerable newborns.

doi.org

Tumor Metabolism: New Frontiers in Diet, Microbiome and Beyond | Keystone Symposia

Join us at the Keystone Symposia on Tumor Metabolism: New Frontiers in Diet, Microbiome and Beyond, June 2026, in Killarney, with field leaders!

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