Daily Sepsis Research Analysis
Three mechanistic sepsis studies advance our understanding of immunothrombosis and inflammatory cell death. New work identifies RING1 as a ubiquitin ligase that restrains GSDMD-driven pyroptosis, shows platelet NLRP6 limits microvascular thrombosis via a TRIM21–TAB1–NF-κB axis, and links fatty acid synthesis to endothelial mtDNA release that activates cGAS–STING in sepsis-induced lung injury.
Summary
Three mechanistic sepsis studies advance our understanding of immunothrombosis and inflammatory cell death. New work identifies RING1 as a ubiquitin ligase that restrains GSDMD-driven pyroptosis, shows platelet NLRP6 limits microvascular thrombosis via a TRIM21–TAB1–NF-κB axis, and links fatty acid synthesis to endothelial mtDNA release that activates cGAS–STING in sepsis-induced lung injury.
Research Themes
- Regulation of pyroptosis via ubiquitination of GSDMD
- Platelet innate immune signaling and immunothrombosis in sepsis
- Metabolic control of endothelial injury through mtDNA release and cGAS–STING
Selected Articles
1. RING1 dictates GSDMD-mediated inflammatory response and host susceptibility to pathogen infection.
The study identifies RING1 as an E3 ligase that directly ubiquitinates GSDMD (K48-linked at K51/K168) to limit pyroptosis. Ring1 deficiency worsened LPS-induced sepsis and Salmonella infection and led to dysregulated responses in tuberculosis, positioning RING1 as a regulator of inflammatory cell death and a potential therapeutic target.
Impact: This work uncovers a nodal control of pyroptosis with direct therapeutic implications for sepsis and infectious diseases by targeting the RING1–GSDMD axis.
Clinical Implications: Modulating RING1 activity could calibrate excessive pyroptosis in septic shock, but strategies must balance pathogen clearance versus immunopathology; biomarkers of RING1/GSDMD activity may aid endotyping.
Key Findings
- RING1, but not RING2, promotes K48-linked ubiquitination of GSDMD at K51 and K168, driving proteasomal degradation and limiting pyroptosis.
- Ring1 knockout mice exhibit increased mortality and bacterial burden with S. typhimurium, exacerbated LPS-induced sepsis, and dysregulated responses to M. tuberculosis.
- Pharmacologic or genetic inhibition of RING1 elevates GSDMD and pyroptotic cell death, nominating RING1 as a potential therapeutic target.
Methodological Strengths
- Multi-model in vivo validation across LPS sepsis and bacterial infections (Salmonella, M. tuberculosis)
- Precise mechanistic mapping including identification of GSDMD ubiquitination sites (K51/K168) and functional consequences
Limitations
- Preclinical models without human interventional data; translational applicability remains to be tested
- Context-dependent effects across pathogens could complicate therapeutic targeting
Future Directions: Develop selective RING1 modulators; define sepsis endotypes with dysregulated RING1–GSDMD signaling; evaluate safety-efficacy trade-offs in large-animal models and early-phase trials.
2. Platelet NLRP6 protects against microvascular thrombosis in sepsis.
Platelet-specific NLRP6 restrains immunothrombosis in sepsis by promoting TRIM21-mediated K48-linked ubiquitination and degradation of TAB1, thereby dampening NF-κB signaling, platelet activation, and NET formation. Loss of platelet NLRP6 worsened survival and microvascular thrombosis in CLP sepsis, highlighting a platelet-intrinsic protective pathway.
Impact: This study uncovers a platelet-intrinsic NLR pathway that limits sepsis-related microthrombosis, providing a mechanistic target to modulate immunothrombosis without broadly suppressing immunity.
Clinical Implications: Therapeutic strategies enhancing platelet NLRP6 function or targeting the TAB1–NF-κB axis may reduce microvascular thrombosis and organ injury in sepsis; human translational studies are warranted.
Key Findings
- Platelet-specific NLRP6 deletion increased mortality and microvascular thrombosis in lung and liver in CLP-induced sepsis.
- NLRP6 promotes TRIM21–TAB1 interaction leading to K48-linked polyubiquitination and degradation of TAB1, restraining platelet NF-κB signaling.
- NF-κB inhibition rescued the prothrombotic phenotype of NLRP6-deficient platelets and improved survival; sepsis plasma triggers NLRP6/TRIM21-dependent TAB1 degradation via TLR4/MyD88.
Methodological Strengths
- Platelet-specific knockout with in vivo CLP sepsis model and survival outcomes
- Mechanistic dissection of TRIM21–TAB1–NF-κB pathway with rescue by NF-κB inhibition and human platelet ex vivo validation
Limitations
- Findings are largely in murine models; limited human validation with sepsis plasma and healthy platelets
- Potential bleeding risks or off-target effects of pathway modulation are not addressed
Future Directions: Define pharmacologic strategies to boost platelet NLRP6 signaling or mimic TAB1 degradation; assess biomarkers of platelet NF-κB activity as predictors of immunothrombosis in sepsis.
3. Fatty acid synthesis promotes mtDNA release via ETS1-mediated oligomerization of VDAC1 facilitating endothelial dysfunction in sepsis-induced lung injury.
Disordered fatty acid synthesis in sepsis drives endothelial dysfunction by promoting ETS1-dependent VDAC1 oligomerization, mtDNA release, and consequent cGAS–STING activation and pyroptosis. Pharmacologic inhibition of fatty acid synthesis attenuated endothelial injury and lung damage in vitro and in vivo.
Impact: This study mechanistically links cellular metabolism to innate DNA sensing and inflammatory cell death in endothelial injury, revealing actionable targets (FASN, VDAC1, cGAS–STING) for sepsis-associated lung injury.
Clinical Implications: Existing inhibitors of fatty acid synthesis or interventions modulating VDAC1–cGAS–STING may be repurposed to limit endothelial injury in septic lung damage; translational biomarker strategies (mtDNA, lipid signatures) could guide patient selection.
Key Findings
- Fatty acid synthesis is markedly dysregulated in patients with sepsis; its inhibition reduces endothelial and lung injury in vitro and in vivo.
- Fatty acid synthesis promotes ETS1-mediated suppression of VDAC1 ubiquitination, enabling VDAC1 oligomerization and mtDNA release.
- Released mtDNA activates cGAS–STING signaling and endothelial pyroptosis, driving inflammatory and coagulation activation.
Methodological Strengths
- Integrated patient observations with mechanistic in vitro and in vivo experiments
- Clear pathway delineation from metabolic perturbation to VDAC1, mtDNA release, cGAS–STING activation, and pyroptosis
Limitations
- Specific inhibitors and dosing regimens require safety and efficacy validation in humans
- Extent of generalizability across sepsis endotypes and other organs remains uncertain
Future Directions: Evaluate FASN/VDAC1/cGAS–STING modulators in large-animal sepsis models; develop translational biomarkers (circulating mtDNA, lipidomics) to stratify patients for metabolic-endothelial targeting.