Daily Sepsis Research Analysis
Mechanistic studies illuminate how platelets fuel immunothrombosis in sepsis via IRAP-driven ribophagy and demonstrate that pharmacologic GSDMD inhibition (JX06) suppresses PANoptosis and multiple-organ injury in vivo. Complementing these basic advances, a nationwide analysis of nearly 3 million US sepsis hospitalizations shows that COVID-19 reversed pre-pandemic gains in post-discharge outcomes and details race/ethnicity-associated differences in long-term nursing home stay or death.
Summary
Mechanistic studies illuminate how platelets fuel immunothrombosis in sepsis via IRAP-driven ribophagy and demonstrate that pharmacologic GSDMD inhibition (JX06) suppresses PANoptosis and multiple-organ injury in vivo. Complementing these basic advances, a nationwide analysis of nearly 3 million US sepsis hospitalizations shows that COVID-19 reversed pre-pandemic gains in post-discharge outcomes and details race/ethnicity-associated differences in long-term nursing home stay or death.
Research Themes
- Immunothrombosis and platelet energy metabolism in sepsis
- PANoptosis-targeted therapeutics for MODS and sepsis
- Population-level outcomes and disparities during the COVID-19 era
Selected Articles
1. IRAP Drives Ribosomal Degradation to Refuel Energy for Platelet Activation during Septic Thrombosis.
This mechanistic study shows that IRAP drives lysosomal degradation of ribosomes (ribophagy) in activated platelets during septic thrombosis, supplying amino acids to glycolysis to sustain energy-intensive activation. Blocking IRAP reduces platelet hyperactivation and septic thrombosis, nominating IRAP as a druggable node linking immunothrombosis and metabolism.
Impact: It uncovers a previously unrecognized energy-regeneration pathway in platelets and identifies IRAP as a therapeutic target to modulate immunothrombosis in sepsis.
Clinical Implications: While preclinical, targeting IRAP could offer a novel adjunct to reduce septic immunothrombosis without broadly suppressing host defenses; translational work and safety profiling are needed.
Key Findings
- IRAP promotes lysosomal degradation of ribosomes (ribophagy) in activated platelets via mTORC1- and S-acylation–dependent mechanisms.
- Amino acids liberated by ribophagy fuel aerobic glycolysis, reprogramming platelet energy metabolism to sustain activation.
- Pharmacologic or targeted blockade of IRAP attenuates platelet hyperactivation and reduces septic thrombosis.
Methodological Strengths
- Mechanistic dissection across molecular, cellular, and in vivo levels linking ribophagy to platelet metabolism.
- Demonstration of causality by perturbing IRAP, with coherent metabolic and functional readouts.
Limitations
- Preclinical study without validation in human clinical cohorts.
- Potential off-target or compensatory pathways were not fully excluded; safety profile of IRAP inhibition is unknown.
Future Directions: Validate IRAP–ribophagy signatures in human sepsis, develop selective IRAP inhibitors/biologics with favorable PK/PD and safety, and test efficacy in sepsis models reflecting clinical heterogeneity.
Platelets play crucial roles in multiple pathophysiological processes after energy-dependent activation. It is puzzling how such a small cellular debris has abundant energy supply. In this study, it is shown that insulin-regulated aminopeptidase (IRAP), a type II transmembrane protein, is a key regulator for platelet activation by promoting energy regeneration during septic thrombosis. Through interaction with certain endosome membrane proteins, IRAP can not only promote granule release, but also facilitate lysosomal degradation of theoretically discarded ribosomes in an mTORC1- and S-acylation-dependent manner in activated platelets. Plentiful amino acids obtained from IRAP-mediated ribophagy are recruited to aerobic glycolysis and then promote energy metabolism reprogramming, thereby producing abundant energy for platelet life extension and prolonged activation. Consequently, targeted blocking IRAP can dramatically alleviate platelet hyperactivation and septic thrombosis.
2. Targeting GSDMD JX06 inhibits PANoptosis and multiple organ injury.
GSDMD is essential for PANoptosis-driven organ injury in heat stress and sepsis models. The small molecule JX06 covalently modifies GSDMD (Cys39/192), prevents GSDMD-NT pore formation, and reduces inflammation, MODS, and mortality in vivo.
Impact: This work provides pharmacologic proof-of-concept that directly targeting GSDMD can suppress PANoptosis and ameliorate MODS, opening a tractable therapeutic avenue for sepsis.
Clinical Implications: GSDMD inhibition could become a targeted adjunctive therapy for sepsis-related MODS, but requires optimization of PK/PD, toxicity, and efficacy across clinically relevant sepsis phenotypes.
Key Findings
- GSDMD deficiency attenuates cell death, inflammation, and multiple organ injury in heat stress and sepsis models.
- JX06 covalently modifies GSDMD at Cys39/192, preventing GSDMD-NT accumulation and pore formation.
- In vivo JX06 suppresses GSDMD-mediated PANoptosis, reducing MODS severity and mortality.
Methodological Strengths
- Convergent genetic (deficiency) and pharmacologic (JX06) approaches establish target validity.
- In vivo efficacy with mechanistic linkage (pore formation and PANoptosis) supports translational relevance.
Limitations
- Preclinical modeling without human clinical validation; unknown off-target risks and long-term safety.
- Pharmacokinetic/pharmacodynamic properties and dosing windows require optimization.
Future Directions: Advance JX06 analogs with optimized PK/PD and safety; evaluate efficacy across sepsis phenotypes and comorbidities; identify biomarkers for patient stratification.
Multiple organ dysfunction syndrome (MODS) is the major cause of mortality of patients in intensive care units. The elusive mechanisms of tissue damage in MODS and limited therapeutic options encourage us to seek effective therapies to MODS. PANoptosis has recently been proven to be the key player in both heat stress and sepsis-mediated MODS. Therefore, we initially investigated the role of gasdermin D (GSDMD) in heat stress and sepsis-induced MODS. We found that GSDMD deficiency attenuates heat stress or sepsis mediated cell death, tissue inflammation and severe multiple organ injury (MOI). Next, we screened out and proved that JX06 effectively inhibited GSDMD-NT mediated cell death, by covalently modifying the Cys39/192 residue in GSDMD, inhibiting the accumulation of GSDMD-NT and pore formation in cell membrane. In vivo, JX06 administration attenuated heat stress and sepsis-mediated cell death, inflammation, MODS and animal mortality via suppressing GSDMD-mediated PANoptosis. Overall, our results indicated that GSDMD is critical for MODS by executing PANoptosis; administrating its inhibitor, JX06, effectively suppresses MODS by inhibiting PANoptosis, and suggesting that JX06 would be an effective drug candidate for MODS and related death.
3. COVID-19 Pandemic and Racial and Ethnic Disparities in Long-Term Nursing Home Stay or Death Following Hospital Discharge.
Among 2,964,517 sepsis hospitalizations of community-dwelling older adults discharged alive, long-term nursing home stay or death declined from 2016 through early 2020 but increased during the pandemic. Black individuals had higher adjusted odds versus non-Hispanic White individuals, whereas Asian/Pacific Islander, Hispanic, and American Indian/Alaska Native had lower odds; pandemic effects did not differ by race/ethnicity.
Impact: This nationwide analysis quantifies shifting post-discharge outcomes in older sepsis survivors and delineates race/ethnicity-associated differences, informing post-acute care planning and equitable health policy during and beyond pandemics.
Clinical Implications: Health systems should anticipate increased post-acute care needs for older sepsis survivors during pandemic surges, embed equitable discharge planning, and target risk mitigation for groups with higher odds of long-term NH stay or death.
Key Findings
- Long-term nursing home stay or death declined from 13.5% (Q1 2016) to 6.9% (Q1 2020), then increased during the pandemic.
- Adjusted odds were higher for Black individuals (aOR 1.33; 95% CI 1.30-1.37) and lower for Asian/Pacific Islander (aOR 0.79), Hispanic (aOR 0.72), and American Indian/Alaska Native (aOR 0.79) versus non-Hispanic White individuals.
- Pandemic period was associated with increasing risk per quarter (aOR 1.03 per quarter), without differential changes by race/ethnicity.
Methodological Strengths
- Massive, linked national datasets with rigorous interrupted time series and adjusted analyses.
- Clear, patient-centered composite outcome with reproducible definitions.
Limitations
- Observational design with potential residual confounding and misclassification of diagnoses or outcomes.
- Generalizability limited to Medicare beneficiaries aged ≥65 years and community-dwelling at baseline.
Future Directions: Identify causal drivers (e.g., care access, facility constraints) and test interventions (transitional care, rehabilitation access) to reduce long-term NH stay or death, integrating social determinants into risk models.
IMPORTANCE: Long-term nursing home stay or death (long-term NH stay or death), defined as new long-term residence in a nursing home or death following hospital discharge, is an important patient-centered outcome. OBJECTIVE: To examine whether the COVID-19 pandemic was associated with changes in long-term NH stay or death among older adults with sepsis, and whether these changes were greater in individuals from racial and ethnic minoritized groups. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used patient-level data from the Medicare Provider Analysis and Review File, the Master Beneficiary Summary File, and the Minimum Data Set. Community-dwelling individuals aged at least 65 years hospitalized with sepsis between January 2016 and June 2021 were included. Data were analyzed from May to November 2024. EXPOSURE: Race and ethnicity and the COVID-19 pandemic. MAIN OUTCOMES AND MEASURES: Patients discharged alive experienced long-term NH stay or death if they resided in a nursing home more than 100 days after hospital discharge and had no period at home greater than 30 days, or died more than 30 days following hospital discharge. Interrupted time series analysis was used to evaluate the association between long-term NH stay or death and the pandemic and race and ethnicity.