Weekly Sepsis Research Analysis
This week’s sepsis literature highlights powerful mechanistic and phenotyping advances alongside pragmatic diagnostic and therapeutic signals. Top papers identify a cardiomyocyte lncRNA (Cpat) that preserves mitochondrial TCA flux in sepsis cardiomyopathy, a platelet kinase (STK10) that drives thromboinflammation and affects survival, and large-scale proteomics that define three validated ARDS inflammatory phenotypes with differential outcomes and heterogeneous treatment effects. Collectively th
Summary
This week’s sepsis literature highlights powerful mechanistic and phenotyping advances alongside pragmatic diagnostic and therapeutic signals. Top papers identify a cardiomyocyte lncRNA (Cpat) that preserves mitochondrial TCA flux in sepsis cardiomyopathy, a platelet kinase (STK10) that drives thromboinflammation and affects survival, and large-scale proteomics that define three validated ARDS inflammatory phenotypes with differential outcomes and heterogeneous treatment effects. Collectively these studies push precision approaches — from molecular targets to phenotype-guided care — and reinforce the need for rapid diagnostics and bedside risk stratification.
Selected Articles
1. Cardiomyocyte lncRNA Cpat maintains cardiac homeostasis and mitochondria function by targeting citrate synthase acetylation.
Preclinical mechanistic work identifies a cardiomyocyte-enriched lncRNA (Cpat) that preserves mitochondrial TCA cycle flux by inhibiting GCN5-mediated citrate synthase acetylation and stabilizing the MDH2–CS–ACO2 complex. Cpat modulation reduced myocardial injury in sepsis-induced cardiomyopathy models, pointing to a metabolic RNA-based therapeutic strategy.
Impact: Reveals a novel RNA-mediated control of mitochondrial metabolism in sepsis cardiomyopathy with a defined enzymatic interaction (GCN5–CS), opening a distinct therapeutic axis beyond anti-inflammatory strategies.
Clinical Implications: Translational interest: targeting Cpat or inhibiting GCN5–citrate synthase acetylation could preserve myocardial metabolism and function in septic cardiomyopathy; requires large-animal validation and early-phase human studies for safety and delivery feasibility.
Key Findings
- Identification of cardiomyocyte-enriched lncRNA Cpat as a regulator of mitochondrial TCA cycle flux.
- Cpat inhibits GCN5-mediated acetylation of citrate synthase, stabilizing the MDH2–CS–ACO2 complex.
- Cpat modulation attenuates myocardial injury in sepsis-induced cardiomyopathy models.
2. STK10 regulates platelet function in arterial thrombosis and thromboinflammation.
Integrated phosphoproteomics and genetic models identify STK10 as a platelet-expressed kinase that directly phosphorylates ILK (Ser343) to regulate aggregation, procoagulant activity, platelet–neutrophil interactions and NET formation. Platelet-specific STK10 deletion reduced thromboinflammation and improved survival in murine sepsis; increased STK10/ILK activation was observed in septic patients.
Impact: Identifies a previously unrecognized platelet kinase pathway that links thromboinflammation to sepsis survival and provides a tractable therapeutic target with translational validation in patient samples.
Clinical Implications: Motivates development of STK10 inhibitors or pathway modulators to mitigate platelet-driven thromboinflammation in sepsis; future work should evaluate safety (bleeding risk) and stratify patients by platelet STK10/ILK activation markers.
Key Findings
- STK10 is expressed in platelets and its deletion impairs hemostasis and arterial thrombosis.
- STK10 directly phosphorylates ILK at Ser343; deletion reduces ILK phosphorylation and platelet activation endpoints.
- Platelet STK10 deletion attenuated platelet–neutrophil interactions, NETs, and thromboinflammation and improved survival in murine sepsis; activation was increased in human sepsis samples.
3. Large-scale proteomic profiling identifies distinct inflammatory phenotypes in Acute Respiratory Distress Syndrome (ARDS): A multi-center, prospective cohort study.
In a prospective multicenter cohort of 1,048 ARDS patients with early serum proteomics, latent class analysis identified and externally validated three inflammatory phenotypes (C1–C3) with distinct mortality, shock rates, ventilator-free days, radiomic lung features, and heterogeneous responses to steroids and ventilation strategies. The study provides validated proteomic classifiers suitable for developing phenotype-stratified trials.
Impact: Large, validated proteomic phenotyping links molecular programs to clinically meaningful ARDS subgroups and heterogeneous treatment effects, providing a direct route to biomarker-stratified interventional trials relevant to sepsis-associated ARDS.
Clinical Implications: Supports development of parsimonious proteomic classifiers for bedside phenotyping and justifies phenotype-stratified randomized trials to test targeted therapies (e.g., steroids, ventilation strategies) in ARDS/sepsis populations.
Key Findings
- Three inflammatory ARDS phenotypes (C1–C3) identified in 1,048 patients and validated in external cohorts.
- Phenotype C1 had highest 90-day mortality, shock incidence and fewest ventilator-free days; C2 had best outcomes.
- Radiomics and pathway enrichment supported biological divergence; heterogeneous treatment effects suggest phenotype-specific responses to glucocorticoids and ventilation.