Daily Sepsis Research Analysis
Analyzed 23 papers and selected 3 impactful papers.
Summary
Two mechanistic studies illuminate organ-specific pathways in sepsis: cardiomyocyte-enriched OTUD5 suppresses NLRP3 inflammasome-driven pyroptosis to mitigate septic cardiomyopathy, while a CXCL10/SLC11A1 neutrophil–macrophage axis and NETs aggravate septic liver injury. Complementing these, a cross-ancestry genetic atlas uncovers shared host-genetic architecture between sepsis and multiple cancers, with directional signals linking lung cancer liability to sepsis.
Research Themes
- Inflammasome regulation and pyroptosis in septic cardiomyopathy (OTUD5–NLRP3 axis)
- Neutrophil–macrophage crosstalk and NETs driving septic liver injury (CXCL10/SLC11A1 axis)
- Shared host-genetic architecture between infections (including sepsis) and cancer across ancestries
Selected Articles
1. Cardiomyocyte-enriched OTUD5 alleviates septic cardiomyopathy by promoting NLRP3 deubiquitination and inhibiting NLRP3 inflammasome activation.
Using in vitro and in vivo sepsis models, the study identifies OTUD5 as a cardiomyocyte-enriched deubiquitinase that directly interacts with NLRP3, promoting its deubiquitination and restraining inflammasome activation. OTUD5 deficiency aggravates septic myocardial injury and pyroptosis, while its overexpression loses benefit in NLRP3-deficient mice, establishing OTUD5→NLRP3 as a critical protective axis.
Impact: Reveals a mechanistic, targetable pathway controlling pyroptosis in septic cardiomyopathy, linking OTUD5-mediated deubiquitination to NLRP3 restraint with strong genetic and functional validation.
Clinical Implications: Positions the OTUD5–NLRP3 axis as a therapeutic avenue; pharmacologic enhancement of OTUD5 activity or selective NLRP3 inhibition may attenuate septic cardiomyopathy. Biomarker development using OTUD5/NLRP3 signaling could aid risk stratification.
Key Findings
- OTUD5 expression is upregulated in myocardial tissue in LPS- and CLP-induced sepsis.
- Cardiomyocyte-specific OTUD5 knockout exacerbates septic myocardial injury and pyroptosis.
- OTUD5 directly interacts with NLRP3; the C224 site promotes deubiquitination and inhibits NLRP3 activation.
- OTUD5 overexpression loses cardioprotective effects in NLRP3 knockout mice, indicating dependency on NLRP3.
Methodological Strengths
- Integrated in vitro cardiomyocyte models and in vivo LPS/CLP sepsis models
- Genetic rigor with cardiomyocyte-specific OTUD5 knockout and AAV9-mediated overexpression, plus substrate validation by co-immunoprecipitation
Limitations
- Preclinical study in rodents; human translational data are not provided.
- Therapeutic modulation of OTUD5 was genetic; pharmacologic feasibility and safety remain untested.
Future Directions: Test small-molecule modulators of OTUD5 or selective NLRP3 inhibitors in large-animal sepsis models and early-phase human studies; explore circulating markers of OTUD5–NLRP3 activity for clinical monitoring.
BACKGROUND: Septic cardiomyopathy (SCM) is the leading cause of mortality among patients diagnosed with sepsis. Nevertheless, the precise mechanisms underlying its pathogenesis remain poorly understood. Deubiquitinating enzymes (DUBs) play a vital role in various cardiovascular diseases. METHODS: This study investigated deubiquitinating enzymes in septic myocardial injury via public RNA-Seq. Pyroptosis was modelled in primary neonatal rat cardiomyocytes using lipopolysaccharide (LPS) and nigericin, with levels assessed by IL‑1β ELISA, Western blot, PI staining, CCK‑8 and LDH assays. Potential substrates of OTUD5 were screened by Co‑immunoprecipitation. Cardiomyocyte‑specific OTUD5‑knockout mice generated by CRISPR/Cas9 were subjected to LPS‑ or Caecal ligation and puncture (CLP)‑induced sepsis models for cardiac function and pyroptosis evaluation. AAV9‑mediated cardiomyocyte‑specific OTUD5 overexpression in NLRP3‑knockout mice was used to validate OTUD5‑NLRP3 functional interaction. RESULTS: This study identifies the deubiquitinating enzyme OTUD5 as being significantly upregulated in myocardial tissue subjected to sepsis induced by LPS and CLP. Cardiomyocyte-specific knockout of OTUD5 leads to exacerbated septic myocardial injury and pyroptosis. Mechanistically, OTUD5 directly interacted with NLRP3, with its C224 site facilitating deubiquitination to inhibit NLRP3 activation. Notably, the protective effects associated with OTUD5 overexpression were lost in NLRP3 knockout mice, underscoring its dependence on NLRP3 for function. CONCLUSIONS: This study has confirmed that OTUD5 inhibits pyroptosis by suppressing the activity of NLRP3, thereby ameliorating septic cardiomyopathy. OTUD5 is worthy of further exploration as a potential therapeutic target for septic cardiomyopathy. KEY POINTS: The expression levels of the deubiquitinating enzyme OTUD5 are elevated in tissues affected by sepsis-induced cardiomyopathy. Cardiomyocyte-specific OTUD5 is a protective factor against myocardial pyroptosis and cardiac dysfunction induced by LPS and CLP. OTUD5 interacts with NLRP3, and its C224 site promotes deubiquitination while inhibiting the activation of NLRP3.
2. A cross-ancestry genetic atlas of shared susceptibility between infectious diseases and cancer.
This cross-ancestry integrative GWAS atlas reveals substantial shared host-genetic architecture between infections and cancers. In Europeans, four orthogonal genome-wide methods concordantly supported sepsis–lung cancer and sepsis–colorectal cancer links; enrichment analyses implicated mucosal/epithelial barriers and immune compartments, and MR suggested directional liability from lung cancer to sepsis.
Impact: Defines pleiotropic loci, genes, and proteins that bridge sepsis with cancers across ancestries, providing mechanistic hypotheses and targets for risk stratification and prevention.
Clinical Implications: While not practice-changing, findings enable hypothesis-driven surveillance in high genetic-liability groups and inform biomarker/target discovery for immune and barrier pathways relevant to sepsis and oncologic outcomes.
Key Findings
- Four complementary genome-wide approaches concordantly supported sepsis–lung cancer and sepsis–colorectal cancer links in Europeans.
- Shared genetic signals were enriched in mucosal/epithelial barrier tissues and immune-cell compartments.
- Identified 396 pleiotropic loci, 14 colocalized variants, 86 high-confidence genes, and 83 pleiotropic proteins (e.g., MORF4L1).
- Exploratory bidirectional Mendelian randomization indicated directional liability from lung cancer to sepsis in Europeans.
Methodological Strengths
- Cross-ancestry integration with multiple orthogonal genome-wide sharing methods
- Multi-layer analyses including tissue/cell-type enrichment, cross-trait loci, proteome integration, and Mendelian randomization
Limitations
- Reliance on GWAS summary statistics may introduce phenotype heterogeneity and residual confounding.
- Mendelian randomization assumptions and limited instrument strength for some traits may affect causal inference.
Future Directions: Validate pleiotropic loci in diverse biobanks with harmonized phenotypes; mechanistically dissect immune/barrier genes in experimental systems; explore clinical risk models integrating genetic liability for infection–cancer intersections.
Extensive epidemiological and mechanistic studies have established links between specific infections and cancer, but the inherited host-genetic contribution to broader infection-cancer relationships remains incompletely characterized. Here, we integrated genome-wide association study summary statistics for multiple infectious diseases and cancers from European- and East Asian-ancestry populations and evaluated shared host genetic architecture across genome-wide and local genetic sharing, tissue- and cell-type enrichment, cross-trait locus discovery, functional gene prioritization, proteome-level integration and exploratory bidirectional Mendelian randomization. In the European ancestry analyses, four complementary genome-wide approaches identified 11, 21, 44 and 11 significant infection-cancer trait pairs, respectively; 11 pairs were supported by at least three approaches, and sepsis-lung cancer, pneumonia-kidney cancer and sepsis-colorectal cancer were supported by all four. In the East Asian-ancestry analyses, tuberculosis-lung cancer showed the most prominent regional shared genetic architecture. Local analyses further showed that genetic overlap was not uniformly distributed across the genome, but was concentrated in specific regions with heterogeneous directions of effect. Tissue- and cell-type enrichment analyses indicated that shared signals were primarily concentrated in mucosal and epithelial barrier-related tissues and immune-cell compartments. Cross-trait analyses identified 396 potential pleiotropic independent risk loci, 14 colocalized variants, and 86 high-confidence pleiotropic genes, while proteome-level analysis identified 83 pleiotropic proteins, including MORF4L1, which was associated with five trait pairs. Exploratory Mendelian randomization provided directional genetic-liability evidence, with the strongest European-ancestry signal linking lung cancer liability to sepsis. Together, these findings support a shared host-genetic component underlying part of the relationship between infections and cancers, involving immune regulation, barrier homeostasis and cellular stress adaptation.
3. CXCL10/SLC11A1 Axis Exacerbates Septic Liver Injury by Regulating Neutrophil Extracellular Traps Formation to Drive Macrophage Pro‑Inflammatory Polarization.
Using CLP sepsis models with bulk and single-cell transcriptomics, the study links neutrophil infiltration and a pro-inflammatory SLC11A1-high phenotype to liver injury severity. The title-supported mechanism indicates a CXCL10/SLC11A1 axis that promotes NETs formation and drives macrophage pro-inflammatory polarization, exacerbating septic liver injury.
Impact: Identifies a neutrophil–macrophage signaling axis and NETs biology as central drivers of septic liver injury, nominating SLC11A1/CXCL10 as actionable nodes.
Clinical Implications: Targeting SLC11A1 or CXCL10, or therapeutically modulating NETs formation and macrophage polarization, may attenuate septic liver injury; transcriptomic markers could inform patient stratification.
Key Findings
- CLP mouse models with bulk and single-cell RNA-seq showed neutrophil infiltration correlating with liver injury severity.
- Sepsis-associated neutrophils exhibited a pro-inflammatory phenotype with specific upregulation of SLC11A1.
- The study leveraged neutrophil-specific conditional Slc11a1 knockout to interrogate function.
- A CXCL10/SLC11A1 axis is implicated in promoting NETs and macrophage pro-inflammatory polarization, worsening liver injury.
Methodological Strengths
- Integration of CLP sepsis models with bulk and single-cell transcriptomics
- Cell-type–specific genetic manipulation (neutrophil Slc11a1 conditional knockout)
Limitations
- Quantitative effect sizes and interventional outcomes are not detailed in the abstract.
- Translational relevance to human sepsis liver injury requires validation.
Future Directions: Assess pharmacologic inhibition of CXCL10/SLC11A1 signaling and NETs modulation in preclinical models; validate SLC11A1-high neutrophil signatures in human septic liver injury.
Intra-abdominal infection frequently progresses to sepsis, where the liver is an early and commonly injured organ. In a cecal ligation and puncture (CLP) mouse model combined with bulk and single‑cell RNA sequencings, we observed marked neutrophil infiltration in the liver that correlated with injury severity. Sepsis‑associated neutrophils displayed a pro‑inflammatory phenotype and specifically upregulated the divalent metal transporter solute carrier family 11 member 1 (SLC11A1). Conditional knockout of Slc11a1 in neutrophils (Ly6G-Cre