The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player in pyroptosis. This recently characterized class of pore-forming effector proteins is pivotal in orchestrating processes such as membrane permeabilization, pyroptosis, and the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants and infections. GSDMs have been implicated in a range of diseases including, but not limited to, sepsis, viral infections, and cancer, either through involvement in pyroptosis or independently of this process. The regulation of GSDM-mediated pyroptosis is gaining recognition as a promising therapeutic strategy for the treatment of various diseases. Current strategies for inhibiting GSDMD primarily involve binding to GSDMD, blocking GSDMD cleavage or inhibiting GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In this review, we delve into the cutting-edge understanding of the interplay between GSDMs and pyroptosis, elucidate the activation mechanisms of GSDMs, explore their associations with a range of diseases, and discuss recent advancements and potential strategies for developing GSDMD inhibitors.

Septic liver injury/failure that is mainly characterized by oxidative stress, inflammation, and apoptosis led to a great part of terminal liver pathology with limited effective intervention. Here, we used a lipopolysaccharide (LPS) stimulation model to simulate the septic liver injury and investigated the effect of sophocarpine on LPS-stimulated mice with endotoxemia. We found that sophocarpine increases the survival rate of mice and attenuates the LPS-induced liver injury, which is indicated by pathology and serum liver enzymes. Further research found that sophocarpine ameliorated hepatic oxidative stress indicators (H₂O₂, O2∙−, and NO) and enhanced the expression of antioxidant molecules such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). In addition, sophocarpine also attenuated regional and systematic inflammation and further reduced apoptosis of hepatocytes. Mechanistic evidence was also investigated in the present study as sophocarpine inhibited hepatic expression of the CYP2E/Nrf2 pathway during oxidative stress, inactivated p38/JNK cascade and NF-κB pathway, and, meanwhile, suppressed PI3K/AKT signaling that reduced apoptosis. Conclusively, the present study unveiled the protective role of sophocarpine in LPS-stimulated oxidative reaction, inflammation, and apoptosis by suppressing the CYP2E/Nrf2/ROS as well as PI3K/AKT pathways, suggesting its promising role in attenuating inflammation and liver injury of septic endotoxemia.

Acute kidney injury (AKI) is a common and serious complication in severe acute pancreatitis (AP), associated with high mortality rate. Early detection of AKI is crucial for prompt intervention and better outcomes. This study aims to develop and validate predictive models using machine learning (ML) to identify the onset of AKI in patients with AP. Patients with AP were extracted from the MIMIC-IV database. We performed feature selection using the random forest method. Model construction involved an ensemble of ML, including random forest (RF), support vector machine (SVM), k-nearest neighbors (KNN), naive Bayes (NB), neural network (NNET), generalized linear model (GLM), and gradient boosting machine (GBM). The best-performing model was fine-tuned and evaluated through split-set validation. We analyzed 1,235 critically ill patients with AP, of which 667 cases (54%) experienced AKI during hospitalization. We used 49 variables to construct models, including GBM, GLM, KNN, NB, NNET, RF, and SVM. The AUC for these models was 0.814 (95% CI, 0.763 to 0.865), 0.812 (95% CI, 0.769 to 0.854), 0.671 (95% CI, 0.622 to 0.719), 0.812 (95% CI, 0.780 to 0.864), 0.688 (95% CI, 0.624 to 0.752), 0.809 (95% CI, 0.766 to 0.851), and 0.810 (95% CI, 0.763 to 0.856) respectively. In the test set, the GBM's performance was consistent, with an area of 0.867 (95% CI, 0.831 to 0.903). The GBM model's precision is crucial, aiding clinicians in identifying high-risk patients and enabling timely interventions to reduce mortality rates in critical care.

Programmed death ligand 1 (PD-L1) is not only an important molecule in mediating tumor immune escape, but also regulates inflammation development. Here we showed that PD-L1 was upregulated on neutrophils in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS). Neutrophil specific knockout of PD-L1 reduced lung injury in ARDS model induced by intratracheal LPS injection. The level of NET release was reduced and autophagy is elevated by PD-L1 knockout in ARDS neutrophils both in vivo and in vitro. Inhibition of autophagy could reverse the inhibitory effect of PD-L1 knockout on NET release. PD-L1 interacted with p85 subunit of PI3K at the endoplasmic reticulum (ER) in neutrophils from ARDS patients, activating the PI3K/Akt/mTOR pathway. An extrinsic neutralizing antibody against PD-L1 showed a protective effect against ARDS. Together, PD-L1 maintains the release of NETs by regulating autophagy through the PI3K/Akt/mTOR pathway in ARDS. Anti-PD-L1 therapy may be a promising measure in treating ARDS.

Cytokine storm is a hallmark for acute systemic inflammatory disease like sepsis. Intrinsic microbiome-derived short-chain fatty acid (SCFAs) like acetate modulates immune cell function and metabolism has been well studied. However, it remains poorly investigated about the effects and the underlying mechanism of exogenous acetate in acute inflammation like sepsis. Here, we observed that serum acetate accumulates in patients undergoing abdominal gastrointestinal surgery and in septic mice. Short exposure to high-dose exogenous acetate protects mice from sepsis by inhibiting glycolysis in macrophages, both in vivo and in vitro. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) stabilization or overexpression reverses the decreased glycolysis and pro-inflammatory cytokine production in macrophages and abrogates acetate’s protective effect in septic mice. Meanwhile, we also found acetyl-CoA synthetase-2, but not GPR41 or GPR43, plays a key role in acetate’s immunosuppressive effect. Acetate transiently increases acetyl-coenzyme A production, promoting histone acetylation and decreasing acetyl-transfer to NF-κB p65. These findings suggest that short exposure to mM-level acetate inhibits macrophage immune response linked to HIF-1α-dependent glycolysis. Taken together, we demonstrate short-term exposure of exogenous acetate could regulate inflammatory responses through attenuating HIF-1α-dependent glycolysis.