Background: Chronic limb-threatening ischemia (CLTI), the most severe form of peripheral artery disease, is marked by ischemic rest pain or tissue loss, and increased risk of major adverse limb and cardiovascular events. Surgery is a pillar of the medical management of CLTI, yet amputation rates remain high after these procedures. Patients with CLTI have poor mitochondrial function and low O 2 availability which drive the accumulation of acetyl-CoA and lactate which are substrates for histone modifications. However, no studies have explored histone modifications in the CLTI limb. To test the hypothesis that mitochondrial dysfunction in CLTI drives epigenetic changes in ischemic muscle, we used a multi-faceted approach. Methods: Patients with CLTI (Rutherford category 4 or 5) undergoing open revascularization (vein bypass) were enrolled. Biopsies were taken from gastrocnemius (ischemic) and quadriceps (non-ischemic) muscles pre-surgery and again five days post-surgery. Additionally, 12-14-week-old C57BL/6J and BALB/cJ mice underwent femoral artery ligation (FAL) and hindlimb muscle was collected 24 hours and seven days post-FAL. Immunoblotting and histological analyses assessed epigenetic changes to quantify histone acetylation, lactylation, and methylation patterns in human and mouse ischemic muscle. Results: In patients with CLTI, ischemic gastrocnemius muscle showed reduced H3K27ac compared to the quadriceps, accompanied by decreased H3K4me3 and H3K9me3 levels. Given strain-specific differences in mitochondrial function and ischemic regeneration following FAL, C57BL/6J and BALB/cJ mice were compared. At 24 hours post FAL, BALB/cJ mice showed significant reductions in H3K18ac ( p< 0.0001), H3K27ac ( p= 0.0173), and H3K18la ( p= 0.0021) in the ischemic limb relative to the control limb. By seven days post-FAL, both C57BL/6J and BALB/cJ mice demonstrated increased H3K18ac ( p= 0.0177 ; p= 0.0001 ) and H3K27ac ( p <0.0001 ; p= 0.0023 ) in the ischemic limb, while methylation changes diverged, with decreased H3K4me3 ( p= 0.0001 ; p= 0.0001 ) and elevated H3K9me3 ( p= 0.0006 ; p< 0.0001 ) in the ischemic limb. Conclusion: Ischemia drives dynamic, time- and strain-dependent remodeling of histone acetylation, lactylation, and methylation in skeletal muscle. Together, these epigenetic shifts suggest that metabolic dysfunction contributes directly to chromatin regulation in CLTI, highlighting epigenetic pathways as potential targets to enhance muscle recovery following revascularization.

Copy number variations (CNVs) are major structural genomic variants that contribute to a wide range of human diseases. Accurate detection of CNVs from whole-exome sequencing (WES) data has been a long-sought goal for clinical and population genetic studies. Despite recent progress, existing WES-based CNV callers still suffer from high false-positive rates and reduced recall for short-length variants, and current deep learning methods have not fully used complementary information in region-level genomic features. Here we present CN-RNN, a deep learning-based CNV caller for WES data. The model combines a bidirectional long short-term memory (BiLSTM) branch that captures local depth changes and contextual dependencies across neighboring exons with a parallel multi-layer perceptron (MLP) branch that encodes region-level metadata such as GC content, mappability, and exon length. CN-RNN was trained on the Autism Sequencing Consortium (ASC) parent-child trio cohort using the Mendelian rule of inheritance to ensure high-quality training sets. It was evaluated across three independent datasets, in which we showed that CN-RNN outperformed existing WES-based CNV callers and deep learning methods. CN-RNN offers a scalable, accurate tool for CNV profiling in WES-based studies and supports broader application of CNV analysis in population and clinical research. CN-RNN is available at https://github.com/FeifeiXiao-lab/CN-RNN.

IntroductionSepsis survivors frequently develop long-term immune dysfunction, but the epigenetic mechanisms underlying persistent myeloid suppression remain unclear. Myeloid-derived suppressor cells (MDSCs), whose function is shaped by host age and sex, are key contributors to post-sepsis immune dysregulation.MethodsHere, we present a high-resolution epigenetic map targeting gene promoters of MDSCs after sepsis and daily chronic stress using MAPit-FENGC, a single-molecule assay that simultaneously profiles DNA methylation and chromatin accessibility. In a clinically relevant murine model, including young and older adult male and female mice, splenic MDSCs were isolated for MAPit-FENGC and single-cell RNA sequencing.ResultsUnsupervised clustering identified nine promoter classes reflecting chromatin dynamics: age- and sex-dependent sepsis-induced opening (Classes 1-4), persistent closure with varying levels of DNA methylation (Classes 5-7), and constitutive openness post-sepsis (Classes 8, 9). Transcriptomic profiling corroborated these promoter states, linking accessibility with gene expression.ConclusionsThese findings define promoter-level epigenetic classes across a targeted locus panel in splenic CD11b+Gr1+ cells within this murine sepsis model and generate mechanistic hypotheses regarding age- and sex-associated chromatin states.

Recent advances in drug discovery have demonstrated that incorporating side information (e.g., chemical properties about drugs and genomic information about diseases) often greatly improves prediction performance. However, these side features can vary widely in relevance and are often noisy and high-dimensional. We propose Bayesian Variable Selection-Guided Inductive Matrix Completion (BVSIMC), a new Bayesian model that enables variable selection from side features in drug discovery. By learning sparse latent embeddings, BVSIMC improves both predictive accuracy and interpretability. We validate our method through simulation studies and two drug discovery applications: 1) prediction of drug resistance in Mycobacterium tuberculosis, and 2) prediction of new drug-disease associations in computational drug repositioning. On both synthetic and real data, BVSIMC outperforms several other state-of-the-art methods in terms of prediction. In our two real examples, BVSIMC further reveals the most clinically meaningful side features.

Background:Genome-wide association studies (GWAS) have identified numerous lung cancer susceptibility loci based on single nucleotide polymorphisms (SNPs), yet a substantial proportion of heritability remains unexplained. We therefore evaluated germline copy number variants (CNVs) as an underexplored source of genetic susceptibility and potential contributors to genomic instability in lung cancer. Methods:We conducted a genome-wide analysis of germline CNVs using 19,342 cases and 15,917 controls from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, with replication in two independent cohorts. High-confidence CNVs were identified by integrating two CNV callers including PennCNV and modSaRa2. Association analyses were performed using both gene-based and CNV region-based approaches. Polygenic risk scores (PRS) were constructed from top loci, and functional validation was conducted using siRNA-mediated knockdown in lung fibroblast cells. Results:We identified CNVs in four genomic regions (1p36.22, 2q31.2, 6p21.32, and 19q13.32) significantly associated with lung cancer risk. Two loci (1p36.22 and 2q31.2) were consistently supported across both analytical strategies. A CNV-based PRS constructed from key genes (CLCN6, NFE2L2, OPA3, and PSMB8) was significantly associated with lung cancer risk and replicated across independent datasets. Functional assays demonstrated that knockdown of NFE2L2 and OPA3 increased endogenous DNA damage, supporting a role in genomic stability. Conclusions:Germline CNVs contribute to lung cancer susceptibility and may influence carcinogenesis through mechanisms related to genomic instability. Impact:These findings expand the genetic architecture of lung cancer and highlight CNVs as potential biomarkers for improving risk stratification and informing precision prevention strategies.

Sepsis disproportionately affects the elderly, and the cellular mechanisms driving age- and sex-dependent lymphoid immune remodeling remain poorly defined. In this work, we mapped the splenic lymphoid transcriptional landscape of young and older adult, male and female mice after sepsis by single-cell RNA sequencing. While both sexual and age dimorphism shaped the baseline lymphocyte composition, the transcriptional reprogramming induced by sepsis was significantly influenced only by age. Sepsis induced a proportional reduction in lymphocytes across age and sex groups; however, aging modified the pattern of lymphocyte reconstitution. Following sepsis, older adult mice displayed an enhanced B cell maturation compared to young mice. Moreover, across all major lymphocyte subtypes, older adult mice demonstrated transcriptionally suppressed metabolic pathways at baseline that shifted to exaggerated activation after sepsis. Furthermore, intercellular communication analysis from antigen-presenting cells to T cells revealed broadly age-dependent activation of co-stimulatory and antigen-presentation pathways after sepsis. Age and sepsis also widely reshaped the druggable landscape in lymphocytes, revealing a distinct predicted drug response profile in older adult mice after sepsis. These data suggest that aging reshapes the lymphoid baseline and the subsequent septic response in ways that may contribute to the poorer outcomes observed in older hosts. Notably, under these conditions, we did not detect significant sexual dimorphism. This lymphoid-specific age-driven transcriptional override highlights specific metabolic and signaling checkpoints as potential targets for precision immunotherapy in older sepsis.

We read with great interest the article by Fleifil et al [...]

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have become a standard of care for estrogen receptor-positive breast cancer and are being developed for other malignancies. However, resistance to these drugs readily develops, limiting their impact on patient survival. Mechanisms of resistance to CDK4/6 inhibition involve multiple changes in gene expression. We investigated the process of tumor cell adaptation to CDK4/6 inhibitors and the impact of selective inhibitors of CDK8/19 Mediator kinases—broad-spectrum regulators of transcriptional reprogramming—on such adaptations. Adaptive non-genetic resistance to CDK4/6 inhibitors develops rapidly, but the addition of CDK8/19 inhibitors prevents the development of this resistance in different tumor models, in vitro and in vivo. RNA sequencing (RNA-seq) analysis reveals that combining CDK4/6 and CDK8/19 inhibitors suppresses many of the adaptation-associated changes in gene expression, including those previously associated with CDK4/6 inhibitor resistance. The findings suggest that CDK8/19 inhibition may greatly extend the therapeutic benefit of CDK4/6 inhibitors.

Abstract Background Prematurity is a leading cause of neonatal and childhood mortality, with infections driving early deaths. Innate immunity provides frontline defense after birth and is shaped in part by myeloid-derived suppressor cells (MDSCs). The role of MDSCs in regulation of neonatal immunity, especially in the context of prematurity, remains elusive. We sought to understand the transcriptional landscape of neonatal immune myeloid regulators, specifically differences between preterm and full-term neonates. Insight into specific cellular networks could help understand how to skew preterm MDSCs’ development towards classical immunotolerant and anti-microbial mechanisms. Methods This cross-sectional study used single-cell RNA sequencing to characterize the neonatal MDSC transcriptional landscape, developmental trajectories, and predicted signaling networks within 48 h after birth. Peripheral blood mononuclear cells were isolated from 7 preterm neonates (< 36 weeks gestational age), 6 full-term neonates (> 37 weeks), and 6 healthy adult (21–45 years old, control). Primary exposure was premature birth and neonatal intensive care hospitalization from a single-center, academic tertiary care hospital between 2023 – 2024. Results Among ~ 339,000 cells, preterm neonates exhibited enrichment of polymorphonuclear MDSCs (10.6% ± 5.3%) vs full-term (2.6% ± 1.3%) and adults (0.4% ± 1.3%). Trajectory analysis identified a prematurity-associated differentiation branch characterized by inflammatory signaling, mitochondrial stress, and heightened protein-translation programs, distinct from a conserved, tolerogenic MDSC trajectory present across ages. Cell-communication modeling showed intensified outgoing and incoming signaling via ADGRE, RESISTIN, TGF-β, ANNEXIN, and ICAM networks. Antigen presentation signatures suggested preserved MHC-I output and diminished MHC-II interactions in neonates, with increased MHC-I input to preterm polymorphonuclear MDSCs. Conclusions Prematurity is associated with early divergence of MDSC maturation toward an inflammatory and metabolically stressed PMN-MDSC state with altered immune communication. These findings identify cellular mechanisms that may contribute to the heightened tissue damage and infection susceptibility of preterm neonates and highlight MDSC signaling as a potential target for early-life immunomodulatory interventions.

Sepsis remains a leading cause of morbidity and mortality worldwide, with survivors often following divergent trajectories: rapid recovery (RAP) or progression to chronic critical illness (CCI). CCI is characterized by persistent organ dysfunction, recurrent infections, and immune dysregulation. Myeloid-derived suppressor cells (MDSCs), which expand in number after sepsis, are implicated in this maladaptive state, yet their epigenetic regulation remains poorly understood. Here, we applied an Omni-ATAC protocol optimized to profile chromatin accessibility in CD66b + MDSCs from healthy participants (HPs) and sepsis patients across time points (day 4, day 14-21, and 6 months) and clinical outcomes (RAP, CCI, and Deceased). Dimensionality reduction analyses of genome-wide chromatin accessibility showed clear separation of sepsis and HP samples. Furthermore, these analyses revealed distinct trajectories post-sepsis diagnosis: RAP samples progressively regained HP-like chromatin states, whereas CCI samples remained epigenetically "locked" in aberrant states. Differential accessibility analysis identified thousands of promoter regions with altered accessibility, including immune checkpoint and inflammatory genes (e.g., ARG1, CD274, S100A8 / 9 ). Pathway analyses predicted global suppression of immune, metabolic, and chromatin remodeling programs in CCI, contrasting with restoration in RAP. These findings from patient-derived CD66b + MDSCs suggest that epigenetic chromatin remodeling underlies divergent recovery trajectories and highlight chromatin-modifying pathways as potential therapeutic targets to restore immune competence in sepsis patients with CCI.

BACKGROUND: Mechanisms driving the development of type A aortic dissection (TAD) are currently poorly understood, and animal models of spontaneous TAD are limited. In the present study, we developed a novel mouse TAD model and evaluated the role of GSDMD (gasdermin D) in TAD development. METHODS: TADs were created by treating the ascending aorta of adult C57BL/6J mice with Act E (active elastase) and β-aminopropionitrile. The temporal progress of the TAD pathology was rigorously characterized by histological evaluation and scanning electron microscopy, while potential mechanisms were explored using bulk RNA sequencing of specimens collected at multiple time points. With this novel TAD model, we conducted additional experiments to investigate the impact of GSDMD deficiency on TAD formation. RESULTS: Ascending aortas challenged with Act E and β-aminopropionitrile developed pathology featuring the early onset of intimomedial tears (complete penetration) and intramural hematomas, followed by progressive medial loss and aortic dilation. Ingenuity pathway analysis and functional annotation of differentially expressed genes suggested that a unique inflammatory microenvironment, rather than general inflammation, promotes the onset of TADs by specifically recruiting neutrophils to the aortic wall. At later stages, T cell–mediated immune injury emerged as the primary driver of pathology. Gsdmd deficiency attenuated medial loss, adventitial fibrosis, and dilation of TADs. This protective effect correlated with a reduced cell death and decreased T-cell infiltration in TADs. Notably, cleaved GSDMD was detected in human TADs but was absent in healthy aortas. CONCLUSIONS: A novel mouse TAD model was developed, specifically targeting the ascending aorta. This model generates a unique microenvironment that activates specific immune cell subsets, driving the onset and subsequent remodeling of TADs. Consistently, Gsdmd deficiency mitigates TAD development, likely by modulating cell death and T-cell responses. This model provides a valuable tool for studying immune injury mechanisms in TAD pathogenesis.

I. M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia, Novosibirsk State University, Novosibirsk, Russia, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia, Agrarian and Technological Institute, Peoples’ Friendship University of Russia, Moscow, Russia, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China, Environmental Health Sciences, Arnold School of Public Health, University of South Carolina, Columbia, SC, United States, Bio-ID Center, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

Sepsis induces profound immune dysregulation, often resulting in chronic critical illness characterized by persistent immunosuppression and poor outcomes. Myeloid-derived suppressor cells (MDSCs) are central mediators of this immunosuppressive phenotype, yet the influence of age and sex on their transcriptional and metabolic states remain poorly understood. Here, we employed single-cell RNA sequencing of splenic leukocytes from young (3-4 months) and older (18-24 months) adult male and female mice subjected to a clinically relevant murine sepsis model to define age- and sex-specific MDSC phenotypes. We identified significant differences regarding age and sex in MDSC expansion, transcriptome, canonical pathway activation, RNA velocity, mitochondrial metabolism, and predicted cell-cell communication after sepsis. Using drug2cell analysis of total leukocytes we also identified cohort-specific drug target profiles. These findings underscore the importance of age and sex in shaping sepsis-induced MDSC biology and suggest that personalized immunomodulatory strategies targeting MDSCs could improve sepsis outcomes.

Background: Chronic limb-threatening ischemia (CLTI), the most severe form of peripheral artery disease (PAD), is marked by ischemic rest pain or tissue loss, affecting 1 in 10 PAD patients, and increasing risks of limb amputation, cardiovascular events, and mortality. Surgical revascularization is a pillar of the medical management of CLTI, yet a thorough understanding of how revascularization impacts limb muscle is lacking. To begin to fill this knowledge gap, we performed temporal single-nuclei multi-omic sequencing (snRNA-seq and snATAC-seq) on calf muscle obtained from CLTI patients before and after revascularization. Methods: Four patients with CLTI (Rutherford category 4 or 5) undergoing open revascularization (vein bypass) were enrolled. Biopsies were taken from gastrocnemius (ischemic) and quadriceps (non-ischemic) muscles pre-surgery, and gastrocnemius biopsies were collected on post-operative day (POD) 1, 5, and 28, with a final quadriceps biopsy on POD28. Nuclei were isolated from 20 samples and 10x Genomics multi-omics was performed. Bioinformatic analysis assessed gene expression and chromatin accessibility. Results: 34,533 high quality nuclei for each snRNA-seq and snATAC-seq dataset were captured after filtering and quality control. SnRNA-seq clustering revealed eleven distinct cell populations. SnATAC-seq datasets were clustered and cell populations were labeled according to the corresponding snRNA-seq 10x barcode cell type. Temporal shifts in cellular abundance were detected in the data, notably an increase in the relative abundance of macrophages between POD0 (8.9%), POD1 (22.7%) and POD5 (36.6%), followed by a decrease at POD28 (31.8%). Type I myonuclei underwent a decrease in relative abundance between POD0 (26.2%) and POD5 (17.9%), with an increase at POD28 (26.8%). Comparatively, satellite cells saw a gradual increase in relative abundance from POD0 (11.1%) through POD1 (18.7%), POD5 (30.5%), to POD28 (39.8%). Differentially expressed gene analysis of myonuclei populations uncovered downregulation of genes ( p<0.05 ) involved in oxidative phosphorylation, adaptive immune response, and ribosome assembly. Conclusion: Single-nuclei multi-omics reveals transcriptional and epigenetic changes during recovery after revascularization, highlighting shifts in cellular composition and gene regulation in CLTI. These provide insights into muscle remodeling, offering potential biomarkers or therapeutic targets to optimize limb recovery and function.

BACKGROUND:The pathogenesis of abdominal aortic aneurysm (AAA) formation involves vascular inflammation, thrombosis formation, and programmed cell death, leading to aortic remodeling. In this study, we deciphered the role of ferroptosis, an excessive iron-mediated cell death in macrophages during aortic inflammation and vascular remodeling in AAA formation. METHODS:Single-cell RNA sequencing analysis was performed on the human AAA tissue database. AAAs were induced in male and female C57BL/6 (wild-type) mice using 2 models with topical elastase or elastase+β-aminopropionitrile, with or without liproxstatin-1, a specific ferroptosis inhibitor, treatment. Aortic diameter, cytokine expression, histology, hallmarks of ferroptosis such as lipid peroxidation and glutathione, and lipid analysis using mass spectrometry were measured in aortic tissue extracts. In vitro studies deciphered the crosstalk of macrophages and smooth muscle cells and analyzed ferroptosis and MMP (matrix metalloproteinase) expressions. RESULTS:Single-cell RNA sequencing analysis demonstrated significant differences in ferroptosis-related genes in macrophages from human AAAs compared with control aortic tissue. Using 2 established murine models of AAA and aortic rupture in wild-type mice, we observed that treatment with liproxstatin-1 significantly attenuated aortic diameter, proinflammatory cytokine production, immune cell infiltration (neutrophils and macrophages), elastic fiber disruption, and increased smooth muscle cell α-actin expression compared with untreated mice. Lipidomic analysis using mass spectrometry shows a significant increase in ceramides and a decrease in intact lipid species levels in murine AAA tissue compared with controls in the murine AAA model. Mechanistically, in vitro studies demonstrate that liproxstatin-1 treatment of macrophages mitigated ferroptosis and MMP9 expression, as well as the crosstalk with aortic smooth muscle cells by downregulating MMP2 secretion. CONCLUSIONS:Taken together, this study demonstrates that pharmacological inhibition by liproxstatin-1 mitigates macrophage-dependent ferroptosis, contributing to the inhibition of aortic inflammation and remodeling during AAA formation.

CISD1, an outer mitochondrial membrane iron-sulfur cluster protein, regulates intracellular iron levels, oxidative stress, and mitochondrial dynamics, playing critical roles in cellular bioenergetics and redox homeostasis. Although CISD1 has been identified as a prognostic biomarker in specific cancers, its broader implications in tumorigenesis, cancer progression, and immunotherapy remain unclear. Given the heterogeneity of cancer and the need for robust biomarkers across cancers, this study conducts the first comprehensive pan-cancer analysis of CISD1 by evaluating its roles in cancer and treatment. We obtained and analyzed data from databases including TCGA, GTEx, THPA, GEPIA2.0, SangerBox, cBioPortal, TIMER2.0, CAMOIP, DAVID, SRPLOT, and TISIDB. Our findings reveal significant alterations in CISD1 expression at both transcriptional and translational levels, as well as gene mutations across multiple cancers, indicating its potential as a diagnostic biomarker and its involvement in cancer development and progression. CISD1 dysregulation is linked to poor clinical outcomes, as shown through its impact on patient prognosis. GO and KEGG analyses show that CISD1 plays critical roles in cellular bioenergetics. Notably, CISD1 expression is significantly correlated with tumor stemness indices, tumor mutation burden, microsatellite instability, and immune checkpoint proteins in multiple cancers, and altered CISD1 levels are also observed in patients responding to immunotherapy, further supporting its role not only in prognosis but also as a key predictor in immunotherapy responses and outcomes. Our findings demonstrate CISD1 as a reliable and promising diagnostic, prognostic, and immunotherapeutic biomarker for multiple cancers, emphasizing its crucial role in cancer biology and potential to guide personalized cancer therapies.

Introduction:Sepsis leads to expansion of myeloid-derived suppressor cells (MDSC) and their subtypes. These normally transitory MDSCs suppress T cell activation and alter T cell cytokine production while simultaneously promulgating systemic low-grade inflammation. Immune metabolism can shape cell responses, regulate immune suppression, and enhance effector activity. Although MDSC metabolism has been extensively studied in cancer, the metabolic phenotype of this heterogeneous population in sepsis remains unclear. Our goal was to assess metabolic flux in blood MDSCs during and after sepsis and to stratify these patients' clinical features and outcome with differences in metabolic flux that may guide treatment decisions. Methods:Peripheral blood mononuclear cells (PBMC) from healthy subjects and sepsis patients at 4 days, 2-3 weeks, and 6 months underwent CD66b+ or CD3+ enrichment, followed by assessment of metabolic flux, flow cytometry, mRNA sequencing, and chromatin accessibility. Results:Mitochondrial basal oxygen consumption rates (OCR) and maximal oxygen consumption rates (SRC, spare respiratory capacity) were decreased in MDSC from septic patients at 4 days after infection and persisted for up to 6 months after sepsis onset. Sepsis was not associated with differences in glycolysis. In contrast, oxidative metabolism in CD3+ T cells was similar between sepsis patients and healthy subjects. Reduced MDSC oxidative metabolism was linked to adverse clinical outcomes. The decline in oxygen consumption from MDSCs in septic patients was also associated with significant reductions in MDSC mitochondrial content. Transcriptomic analysis of CD66b+ cells isolated from PBMC of healthy participants and patients with sepsis at 4 days, 2-3 weeks, and 6 months revealed 19 differentially expressed genes and three long non-coding RNAs as potentially responsible for this decline in mitochondrial mass. Specifically, NR4A3, NR4A2, and TAMLIN/NR4A1 expression, all critical for mitochondrial biogenesis, were persistently decreased with reduced chromatin accessibility indicative of gene silencing. Discussion:After sepsis, blood CD66b+ cells present with reduced mitochondrial mass and oxidative metabolism that continue at least 6 months after sepsis. These changes in mitochondrial function result from a reduced content of these organelles. We have also identified gene silencing, reduced gene expression of key transcription factors that regulate mitochondrial biogenesis, as well as increased long non-coding RNA as potential drivers of this unique metabolic phenotype. These results highlight the potential benefit of targeting metabolism in sepsis to promote immune homeostasis and recovery.