Daily Sepsis Research Analysis
Analyzed 45 papers and selected 3 impactful papers.
Summary
Mechanistic and clinical advances in sepsis highlight immune cell-death regulation and potential benefits of chronic cardiometabolic therapies. A preclinical study uncovers RETREG1/FAM134B-driven ERGICphagy as a brake on dendritic-cell pyroptosis via STING1–CASP3–GSDME, while another identifies BIRC3–NOC2L–p53(K382) acetylation as a necroptosis driver in sepsis-associated AKI. Clinically, prior SGLT2 inhibitor use in a large veteran cohort was linked to lower 90-day mortality and AKI, albeit with higher euglycemic DKA risk.
Research Themes
- Immune cell-death pathways (pyroptosis/necroptosis) in sepsis
- Cardiorenal protection from chronic SGLT2 inhibitor use in sepsis
- Organelle-selective autophagy (ERGICphagy) and STING signaling
Selected Articles
1. RETREG1/FAM134B-mediated ERGICphagy regulates GSDME-dependent dendritic cell pyroptosis during sepsis.
RETREG1/FAM134B upregulation preserves immune function during sepsis by limiting dendritic-cell pyroptosis via the STING1–CASP3–GSDME axis. Loss of RETREG1 impairs ERGIC-selective autophagy (ERGICphagy), aberrantly activating STING1 and triggering GSDME-dependent pyroptosis. These findings nominate RETREG1–ERGICphagy and STING signaling as actionable nodes to prevent sepsis-induced immune dysfunction.
Impact: Reveals a previously unappreciated organelle-selective autophagy pathway (ERGICphagy) that directly governs dendritic-cell pyroptosis in sepsis, linking autophagy to STING signaling and GSDME. Identifies tractable targets for immunomodulation.
Clinical Implications: Suggests that enhancing RETREG1-mediated ERGICphagy or dampening STING1 activation could prevent immune paralysis in sepsis. Translation will require validation in human cells/tissues and assessment of infection control versus immunosuppression balance.
Key Findings
- RETREG1 upregulation during sepsis is associated with preserved immune function and reduced dendritic-cell pyroptosis.
- RETREG1 deficiency activates the CASP3–GSDME pathway, aggravating pyroptosis and immune dysfunction.
- Defective ERGICphagy leads to aberrant STING1 activation, which drives CASP3–GSDME-dependent pyroptosis.
Methodological Strengths
- Mechanistic dissection across organelle-selective autophagy, STING signaling, and pyroptosis effectors (CASP3–GSDME).
- Use of genetic perturbation to establish causal links (RETREG1 depletion) with phenotypic readouts.
Limitations
- Preclinical models limit direct clinical generalizability.
- Abstract truncation precludes full visibility on rescue or validation experiments in human tissues.
Future Directions: Validate RETREG1–ERGICphagy–STING1 signaling in human sepsis samples; explore small-molecule or biologic modulators of ERGICphagy/STING to mitigate immune dysfunction without impairing pathogen clearance.
During the development of sepsis, aberrant dendritic cell (DC) pyroptosis results in a significant decrease in the numbers of DCs and immune dysfunction. However, the molecular mechanisms regulating DC pyroptosis in sepsis remain unclear. Emerging evidence indicates that RETREG1/FAM134B (reticulophagy regulator 1) is involved in the regulation of programmed cell death to maintain cell viability. Therefore, this study aimed to investigate the potential role and regulatory pathways of RETREG1 in DC death during sepsis. We found that the upregulation of RETREG1 upon septic challenge was intimately associated with the maintenance of immune function. Depletion of RETREG1 in DC significantly aggravated DC pyroptosis and sepsis-induced immune dysfunction by activating the CASP3 (caspase 3)-GSDME (gasdermin E) signaling pathway. Mechanistically, defective RETREG1 expression inhibited autophagic degradation of the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), resulting in abnormal activation of STING1 (stimulator of interferon response cGAMP interactor 1), which further induced CASP3-GSDME-dependent pyroptosis. Genetic downregulation of
2. Association Between Gliflozins Use and Outcomes in Adults with Sepsis: A Multicenter Retrospective Cohort Study Among Veterans.
In a propensity-matched VA multicenter cohort, prior SGLT2 inhibitor use was associated with markedly lower 90-day mortality and AKI in sepsis, with no effect on MACE, shorter hospital stays, but higher euglycemic DKA risk. Findings suggest chronic organ protection may confer resilience when sepsis occurs.
Impact: Largest real-world evaluation to date linking chronic SGLT2 inhibitor exposure with improved sepsis outcomes, using advanced causal inference techniques. Raises actionable questions on continuation policies and targeted monitoring during sepsis.
Clinical Implications: Do not initiate SGLT2i in acute sepsis, but prior users may derive organ-protective benefits; consider avoiding unnecessary early discontinuation while closely monitoring for euglycemic DKA. Prospective trials are needed to inform peri-sepsis management.
Key Findings
- Prior SGLT2i use reduced 90-day mortality (OR 0.591, 95% CI 0.557–0.628).
- Lower risks of AKI (OR 0.862) and MAKE-30 (OR 0.725); no association with MACE.
- Shorter hospital stays but a significantly increased risk of euglycemic DKA (OR 2.371).
Methodological Strengths
- Very large multicenter dataset with 1:4 propensity matching and SuperLearner-based sensitivity analysis.
- Clinically relevant hard endpoints (90-day mortality, AKI, MAKE-30) and pharmacy-verified exposure definition.
Limitations
- Observational design with potential residual confounding and healthy-user bias.
- Generalizability limited by predominantly older male veteran population; adherence uncertainty despite fill records.
Future Directions: Randomized or pragmatic trials to test continuation strategies during sepsis; mechanistic studies on renal/hemodynamic effects; risk-stratified monitoring protocols for euglycemic DKA.
BACKGROUND: Sodium-glucose-cotransporter-2 inhibitors (SGLT2i) improve cardiorenal outcomes in patients with diabetes, chronic heart failure or kidney disease, but their effects in acute settings are unknown. This study evaluated the impact of SGLT2i use on 90-day mortality, major adverse cardiovascular events (MACE), and acute kidney injury (AKI) in patients with sepsis. METHODS: A propensity-matched, multicenter retrospective cohort study was conducted using the Veterans Affairs Healthcare System (VAHCS) National Registry from January 1, 2017, to December 31, 2023. Adult veterans with sepsis using SGLT2i in the year prior to admission were compared to a 1:4 matched control group, adjusting for demographics, comorbidities, medications, and sepsis characteristics. We conducted a sensitivity analysis using SuperLearner to estimate the propensity score and perform matching. Chronic SGLT2i use was defined as ≥3 outpatient fills or <180-day gap from the last fill according to the VAHCS pharmacy registries. Primary outcome was 90-day mortality; secondary outcomes included MACE within 90 days, AKI, MAKE-30, EDKA, and hospital length of stay. RESULTS: Among 197,879 eligible patients, 5.15% were SGLT2i prior users and 94.85% were non-users. After propensity-matching, 10,200 SGLT2i users (mean [SD] age: 70.0 [9.1]; 97.5% male, and 72.4% white) were compared to 37,785 controls (mean [SD] age: 70.2 [9.4]; 97.3% male, and 72.5% white). SGLT2i prior use was associated with a significantly reduced risk of 90-day mortality (OR = 0.591, 95% CI: 0.557-0.628), AKI (OR = 0.862, 95% CI: 0.809-0.918), and MAKE-30 (OR = 0.725, 95% CI: 0.683-0.771). There was no association between SGLT2i use and MACE (OR = 0.986, 95% CI: 0.931-1.044). SGLT2i users had shorter hospital stays (13.4 vs. 18.1 days). However, SGLT2i use was associated with a significantly increased risk of EDKA (OR = 2.371, 95% CI: 2.106-2.671). CONCLUSION: SGLT2i users prior to hospitalization for sepsis had reduced risk of 90-day mortality and AKI, suggesting chronic organ protection decreases the risk of organ failure when sepsis develops.
3. BIRC3 and NOC2L synergistically promote P53 acetylation to accelerate necroptosis in sepsis-associated acute kidney injury.
Transcriptomics and mechanistic experiments identify BIRC3 as an inducer of necroptosis in SA-AKI, with Birinapant attenuating injury. BIRC3 interacts with NOC2L and promotes p53 K382 acetylation, overcoming NOC2L’s inhibitory effect to drive necroptosis. The BIRC3–NOC2L–p53(K382) axis emerges as a druggable pathway in SA-AKI.
Impact: Defines a previously unrecognized p53 acetylation–driven necroptosis mechanism in septic AKI and demonstrates pharmacologic mitigation with a BIRC3 inhibitor. Provides concrete molecular targets for intervention.
Clinical Implications: Supports exploration of BIRC3 inhibition (e.g., birinapant) or modulation of p53 K382 acetylation to limit SA-AKI progression; translational studies and safety profiling are required.
Key Findings
- BIRC3 is upregulated in SA-AKI kidneys and drives necroptosis and inflammation.
- Birinapant (BIRC3 inhibitor) attenuates necroptosis and inflammatory responses in SA-AKI models.
- BIRC3 interacts with NOC2L to promote p53 K382 acetylation, overriding NOC2L’s inhibition and accelerating necroptosis.
Methodological Strengths
- Integrated transcriptomics with mechanistic validation (confocal microscopy, Co-IP/MS, functional assays).
- Pharmacologic intervention (birinapant) provides proof-of-concept targetability.
Limitations
- Predominantly animal and cellular models; human validation is pending.
- Downstream clinical efficacy and safety of BIRC3/p53 acetylation modulation remain untested in sepsis.
Future Directions: Validate the BIRC3–NOC2L–p53(K382) axis in human SA-AKI biopsies; evaluate birinapant or next-generation BIRC3 modulators in translational models; assess combinatorial strategies with anti-inflammatory agents.
Sepsis-associated acute kidney injury (SA-AKI), defined as AKI occurring within 7 days after the onset of sepsis, is more common in critically ill patients and is strongly associated with poor prognosis. To investigate the relationship between cell death and SA-AKI, we used mRNAseq assays in SA-AKI rat kidneys. Sequencing results showed significant up-regulation of baculovirus-containing IAP repeat sequence 3 (BIRC3) and multiple forms of programmed cell death, including necroptosis, which were also verified. Meanwhile, Birinapant, an inhibitor of BIRC3, attenuated necroptosis and inflammatory responses. Furthermore, using laser confocal microscopy and coupled immunoprecipitation coupled mass spectrometry (Co-IP/MS), we identified the intercalating protein of BIRC3, NOC2 like Nucleolar Associated Transcriptional Repressor (NOC2L), for the first time. Apoptosis was quantified by flow cytometry, Annexin V-FITC, and mitochondrial membrane potentials, and cellular damage was examined by projected electron microscopy. Because NOC2L can inhibit P53 acetylation, we further investigated how P53 acetylation regulates necroptosis in SA-AKI and preliminarily discovered that BIRC3 promotes acetylation at the P53-K382 site. Concurrently, BIRC3's promotion of p53 acetylation outweighs NOC2L's inhibition of this process, and both molecules jointly regulate p53-K382 acetylation to drive downstream necroptosis. This study confirms that BIRC3 induces necroptosis in renal cells and accelerates kidney disease progression. Preliminary evidence confirms that BIRC3 promotes p53 acetylation at the K382 site. Furthermore, BIRC3 and its interacting protein NOC2L synergistically regulate p53 acetylation, thereby promoting downstream necroptosis. BIRC3 and NOC2L may serve as potential therapeutic targets for SA-AKI, offering novel therapeutic strategies.