Liver injury is an independent risk factor for multiple organ dysfunction and high mortality in patients with sepsis. However, the pathological mechanisms and therapeutic strategies for sepsis-associated liver injury have not been fully elucidated. Time-restricted feeding (TRF) is a promising dietary regime, but its role in septic liver injury remains unknown. Using 16S rRNA gene sequencing, Q200 targeted metabolomics, transcriptomics, germ-free mice, Hmgcs2/Lpin1 gene knockout mice, and Aml12 cells experiments, we revealed that TRF can mitigate septic liver injury by modulating the gut microbiota, particularly by increasing Lactobacillus murinus (L. murinus) abundance, which was significantly reduced in septic mice. Further study revealed that live L. murinus could markedly elevate serum levels of metabolite 3-hydroxybutyrate (3-HB) and alleviate sepsis-related injury, while the knockout of the key enzyme for 3-HB synthesis (3-hydroxy-3-methylglutaryl-CoA synthase 2, Hmgcs2) in the liver negated this protective effect. Additionally, serum 3-HB levels were significantly positively correlated with L. murinus abundance and negatively correlated with liver injury indicators in septic patients, demonstrating a strong predictive value for septic liver injury (AUC = 0.8429). Mechanistically, 3-HB significantly inhibited hepatocyte ferroptosis by activating the PI3K/AKT/mTOR/LPIN1 pathway, reducing ACSL4, MDA, LPO, and Fe2+ levels. This study demonstrates that TRF reduces septic liver injury by modulating gut microbiota to increase L. murinus, which elevates 3-HB to activate PI3K/AKT/mTOR/LPIN1 and inhibit hepatocyte ferroptosis. Overall, this study elucidates the protective mechanism of TRF against septic liver injury and identifies 3-HB as a potential therapeutic target and predictive biomarker, thereby providing new insights into the clinical management and diagnosis of septic liver injury.

Glutamine (Gln) and leucine (Leu) are amino acids known for modulating various biological functions. This study aimed to identify metabolism-related genes and their transcriptional pattern changes after Gln and/or Leu administration using next-generation sequencing technology in the liver during sepsis, a condition known to lead to liver metabolic reprogramming and damage.

C57BL/6J mice were randomly assigned to a sham control group (C) and four septic groups subjected to cecal ligation and puncture (CLP). The septic groups were as follows: S group, sepsis control with saline injection after CLP; Gln group, injected with Gln after CLP; Leu group, injected with Leu after CLP; and GL group, injected with Gln plus Leu after CLP. All mice were sacrificed on day 4 after the operation, and liver samples were collected for further analysis.

Gln and/or Leu administration during sepsis significantly altered the hepatic transcriptome with different gene expression patterns. Notably, the G group had the highest number of gene changes among the amino acid-treated groups. Gln administration was associated with more pronounced downregulation of leukocyte inflammatory genes. Carbohydrate metabolic pathways were suppressed, but the oxidative phosphorylation pathway was enhanced by Gln administration, potentially improving metabolic reprogramming during sepsis.

Gln and/or Leu treatment showed promise in alleviating sepsis-induced liver injury; however, only Gln administration alone demonstrated beneficial effects on hepatic macronutrient and energy metabolism during sepsis. These results highlight the potential therapeutic significance of specific amino acids on attenuating hepatic metabolic dysregulation and injury in septic insult.

Sepsis-associated liver injury (SLI) is a common complication of sepsis, for which effective therapeutic strategies are lacking. DNA methylation and hydroxymethylation play crucial roles in the regulation of gene expression. This study investigated the effects of metformin on the DNA methylation landscape in a rat model of cecal ligation and puncture (CLP)-induced SLI. Reduced representation bisulfite sequencing (RRBS) and oxidative RRBS (ox-RRBS) were used to assess global DNA methylation and hydroxymethylation patterns in the liver tissues. The results showed that CLP-induced SLI was associated with global DNA hypomethylation and hyperhydroxymethylation, which were partially reversed by metformin treatment. The expression levels of DNA methyltransferases and ten-eleven translocation 2 (TET2) were elevated in the CLP group and were modulated by metformin. Functional enrichment analysis of differentially methylated and hydroxymethylated genes revealed their involvement in oxidative phosphorylation and metabolic pathways. Furthermore, integration of DNA methylation, hydroxymethylation, and transcriptome data identified two genes, A1cf and Atxn7l1, that exhibited increased methylation and decreased expression in CLP, which were reversed by metformin treatment. These findings provide novel insights into the epigenetic mechanisms underlying SLI and suggest that metformin exerts hepatoprotective effects by modulating DNA methylation and hydroxymethylation.

Acute liver injury (ALI) is a prevalent inflammatory disease with no currently available effective targeted therapies that characterized by high mortality and morbidity. Dihydroartemisinin (DHA), a derivative of the renowned antimalarial compound artemisinin, has garnered attention for its anti-inflammatory property. However, the precise anti-inflammatory mechanisms underlying its efficacy in treating ALI remain unclear. Notably, the excessive inflammatory cytokines secreted by macrophages represents a critical factor of liver damage. In our comprehensive study, transcriptome and proteomic analysis of M1 macrophages after DHA treatment was performed to unearth the potential anti-inflammatory targets for ALI treatment. Transcriptomics analysis indicated that DHA significantly mitigated inflammation, primarily by downregulating the expressions of CCL1, CCL2, CCL7, CCL13, and CXCL13. Concurrently, proteomics analysis identified six proteins, such as CYBA and CYBB, that were consistently downregulated in the DHA intervention groups compared to the M1 group. Intriguingly, a protein-protein interaction network analysis highlighted the close association of CYBA and CYBB with the aforementioned chemokine genes. Through meticulous screening, DHA curtailed the production of reactive oxygen species (ROS) by targeting CYBA and CYBB, subsequently suppressing the secretion of several chemokines and dampening the inflammatory response in M1 macrophages. More importantly, DHA not only reduced ROS and chemokine levels but also restored liver function by downregulating CYBA and CYBB to inhibit NF-κB pathway in ALI mice, demonstrating strong anti-inflammatory effects. In conclusion, our findings throw novel light into the underlying anti-inflammatory mechanism of DHA in ALI management, offering valuable insights for future clinical research and therapeutic strategies for inflammatory diseases.

In 2020, sepsis has been defined a worldwide health major issue (World Health Organization). Lung, urinary tract and abdominal cavity are the preferred sites of sepsis-linked infection. Research has highlighted that the advancement of sepsis is not only related to the presence of inflammation or microbial or host pattern recognition. Clinicians and researchers now recognized that a severe immunosuppression is also a common feature found in patients with sepsis, increasing the susceptibility to secondary infections. Lipopolysaccharides (LPS) are expressed on the cell surface of Gram-negative, whereas Gram-positive bacteria express peptidoglycan (PGN) and lipoteichoic acid (LTA). The main mechanism by which LPS trigger host innate immune responses is binding to TLR4-MD2 (toll-like receptor4-myeloid differentiation factor 2), whereas, PGN and LTA are exogenous ligands of TLR2. Nucleotide-binding oligomerization domain (NOD)-like receptors are the most well-characterized cytosolic pattern recognition receptors, which bind microbial molecules, endogenous by-products and environmental triggers. It has been demonstrated that high-density lipoproteins (HDL), besides their major role in promoting cholesterol efflux, possess diverse pleiotropic properties, ranging from a modulation of the immune system to anti-inflammatory, anti-apoptotic, and anti-oxidant functions. In addition, HDL are able at i) binding LPS, preventing the activating of TLR4, and ii) inducing the expression of ATF3 (Activating transcription factor 3), a negative regulator of the TLR signalling pathways, contributing at justifying their capacity to hamper infection-based illnesses. Therefore, reconstituted HDL (rHDL), constituted by apolipoprotein A-I/apolipoprotein A-IMilano complexed with phospholipids, may be considered as a new therapeutic tool for the management of sepsis.

Sepsis-associated liver injury (SALI) is a severe complication of sepsis that contributes to increased mortality and morbidity. Early identification of SALI can improve patient outcomes; however, sepsis heterogeneity makes timely diagnosis challenging. Traditional diagnostic tools are often limited, and machine learning techniques offer promising solutions for predicting adverse outcomes in patients with sepsis.

This study aims to develop an explainable machine learning model, incorporating stacking techniques, to predict the occurrence of liver injury in patients with sepsis and provide decision support for early intervention and personalized treatment strategies.

This retrospective multicenter cohort study adhered to the TRIPOD+AI (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis, Extended for Artificial Intelligence) guidelines. Data from 8834 patients with sepsis in the Medical Information Mart for Intensive Care IV (MIMIC-IV) database were used for training and internal validation, while data from 4236 patients in the eICU-Collaborative Research Database (eICU-CRD) database were used for external validation. SALI was defined as an international normalized ratio >1.5 and total bilirubin >2 mg/dL within 1 week of intensive care unit admission. Nine machine learning models-decision tree, random forest (RF), extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM), support vector machine, elastic net, logistic regression, multilayer perceptron, and k-nearest neighbors-were trained. A stacking ensemble model, using LightGBM, XGBoost, and RF as base learners and Lasso regression as the meta-model, was optimized via 10-fold cross-validation. Hyperparameters were tuned using grid search and Bayesian optimization. Model performance was evaluated using accuracy, balanced accuracy, Brier score, detection prevalence, F1-score, Jaccard index, κ coefficient, Matthews correlation coefficient, negative predictive value, positive predictive value, precision, recall, area under the receiver operating characteristic curve (ROC-AUC), precision-recall AUC, and decision curve analysis. Shapley additive explanations (SHAP) values were used to quantify feature importance.

In the training set, LightGBM, XGBoost, and RF demonstrated the best performance among all models, with ROC-AUCs of 0.9977, 0.9311, and 0.9847, respectively. These models exhibited minimal variance in cross-validation, with tightly clustered ROC-AUC and precision-recall area under the curve distributions. In the internal validation set, LightGBM (ROC-AUC 0.8401) and XGBoost (ROC-AUC 0.8403) outperformed all other models, while RF achieved an ROC-AUC of 0.8193. In the external validation set, LightGBM (ROC-AUC 0.7077), XGBoost (ROC-AUC 0.7169), and RF (ROC-AUC 0.7081) maintained strong performance, although with slight decreases in ROC-AUC compared with the training set. The stacking model achieved ROC-AUCs of 0.995, 0.838, and 0.721 in the training, internal validation, and external validation sets, respectively. Key predictors-total bilirubin, lactate, prothrombin time, and mechanical ventilation status-were consistently identified across models, with SHAP analysis highlighting their significant contributions to the model's predictions.

The stacking ensemble model developed in this study yields accurate and robust predictions of SALI in patients with sepsis, demonstrating potential clinical utility for early intervention and personalized treatment strategies.

Sepsis is characterized by a systemic inflammation disorder and multi-organ dysfunction caused by infection. Glucocorticoids (GCs), as anti-inflammatory properties drugs, are widely used for the management of patients with inflammatory diseases, including sepsis. However, the therapeutic effect and underlying mechanisms of GCs on sepsis remain incompletely understood.

Mouse sepsis models were constructed using intraperitoneal injection of lipopolysaccharide (LPS) and treated with synthetic GC dexamethasone (DEX). Systemic inflammation and organ injury were evaluated by histological staining, immunophenotypic analysis, and detection of inflammatory cytokines. Inflammatory signaling pathways were identified by western blot (WB) and RT-qPCR. Finally, targeted metabolomics were conducted to examine metabolic changes.

Subcutaneous administration of DEX significantly alleviate LPS-induced acute organ injury and systemic inflammation, thereby reducing mortality in septic mice. DEX substantially reduced the amounts of intrahepatic neutrophils/macrophages, and inflammatory cytokines expressions in the livers of septic mice and in LPS-stimulated bone-marrow-derived macrophages (BMDMs). Mechanistically, DEX inhibit JAK1/STAT3 signaling pathway both in livers and BMDMs. Pharmacological inhibition of JAK1 or STAT3 via Upadacitinib or Stattic, respectively, partially mimic the anti-inflammatory function of GC, including the reduction of intrahepatic macrophages, proinflammatory cytokines production, and mortality in septic mice. Additionally, DEX could also promote the rewiring of tricarboxylic acid (TCA) cycle in the livers of septic mice.

This study provides important insights into the molecular and metabolic mechanisms underlying GCs-mediated anti-inflammatory reactions.

Sepsis is a life-threatening multiple organ dysfunction resulting from a dysregulated host response to infection, and patients with sepsis always exhibit a state of immune disorder characterized by both overwhelming inflammation and immunosuppression. The aging of immune system, namely "immunosenescence", has been reported to be correlated with high morbidity and mortality in elderly patients with sepsis. Initially, immunosenescence was considered as a range of age-related alterations in the immune system. However, increasing evidence has proven that persistent inflammation or even a short-term inflammatory challenge during sepsis could trigger accelerated aging of immune cells, which might further exacerbate inflammatory cytokine storm and promote the shift towards immunosuppression. Thus, premature immunosenescence is found in young sepsis individuals, which further aggravates immune disorders and induces the progression of sepsis. Furthermore, in old sepsis patients, the synergistic effects of both sepsis and aging may cause immunosenescence-associated alterations more significantly, resulting in more severe immune dysfunction and a worse prognosis. Therefore, it is necessary to explore the potential therapeutic strategies targeting immunosenescence during sepsis.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by high morbidity and mortality rates. Bacterial infection is a frequent precipitating factor and complication in ACLF patients, significantly worsening patient outcomes. Elucidating the mechanisms underlying bacterial infections and their impact on ACLF pathophysiology is crucial for developing effective therapies to reduce infection rates and mortality. Current research highlights that immune suppression in ACLF increases susceptibility to bacterial infections, which in turn exacerbate immune dysfunction. However, a comprehensive review summarizing the emerging mechanisms underlying this immunosuppression is currently lacking. This review aims to provide an overview of the latest research, focusing on alterations in the immune responses of innate immune cells-including monocytes, macrophages, and neutrophils-as well as adaptive immune cells such as T and B lymphocytes during the onset and progression of bacterial infections in ACLF. In addition, recent advances in immunomodulatory therapies, including stem cell-based interventions, will also be discussed.

Mitochondrial dysfunction frequently occurs in critically ill patients and is thought to contribute to metabolic shutdown and hepatic or gastrointestinal failure. In addition to hypoxemia and inflammation, sedatives are considered potential contributors to further impairment of mitochondrial function.

This study investigated the effect of the sedatives midazolam and dexmedetomidine on liver and colon mitochondrial function. Especially colon mitochondrial affection by both drugs was evaluated here for the first time.

Liver and colon tissue homogenates from healthy Wistar rats (n=60) were treated with therapeutical and supra-therapeutical doses of midazolam (0.25, 5, 50, 100, 500 μM) and dexmedetomidine (1, 5, 50, 100, 1000 nM). Samples were analyzed using the Clark electrode (Strathkelvin 782). Data analyses were performed via GraphPad Prism® 8 using the Kruskal-Wallis + Dunn's post-hoc test. p < 0.05 was considered significant.

In liver homogenates, treatment with 500 μM midazolam (48.6 ± 6.6 %) showed a significantly decreased respiratory control index (RCI) compared with the control (107.1 ± 14.8 %, p < 0.01) for complex II but without decreases in ADP:O ratio. Colon homogenate did not show significant alterations after midazolam treatment. Dexmedetomidine treatment did not affect colon or liver mitochondrial respiration in any dosage.

In clinical dosages on healthy organs, midazolam and dexmedetomidine did not show any effects on mitochondrial respiration in the colon and liver. However, in supra-therapeutical dosages, midazolam showed an organ-specific, dose-dependent, and complex-dependent effect on mitochondrial respiration by reducing the coupling of ETS and OXPHOS but without decreasing efficacy.

Severe fever with thrombocytopenia syndrome (SFTS) is a widely prevalent infectious disease caused by severe fever with thrombocytopenia syndrome virus (SFTSV). SFTSV infection carries a high mortality rate and has emerged to be a public health concern. SFTSV infection could induce many classical cell death pathways. Ferroptosis, a novel iron-dependent form of regulated cell death, is shown to participate in various biological processes and is considered as a new therapeutic target. In the current study, we reported that SFTSV infection perturbed the classical redox cycle by downregulating the expression of GPX4, SLC7A11 and GSH, and increasing the level of reactive oxygen species (ROS) and malondialdehyde (MDA). Interestingly, we observed that the elevation of ATG5 mRNA m6A modification after SFTSV infection and mutation of the m6A-sites significantly rescued SFTSV infection-induced ferritinophagy. We further found that the NSs protein of SFTSV played a major role in driving the ferritinophagy. Finally, we found that ferroptosis inhibitor ferrostatin-1 prevented ferroptosis and suppressed SFTSV infection both in vitro and in vivo models. In summary, our study demonstrated that SFTSV infection could induce ferroptosis in liver, and m6A modified ATG5 mediated ferritinophagy to facilitate this process. Targeting ferroptosis may serve as a potential therapy for the treatment of SFTS.Abbreviations: ATG5: autophagy related 5; Baf-A1: bafilomycin A1; Fer-1: ferrostatin-1; Fe2+: ferrous iron; FTH1: ferritin heavy chain 1; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic - pyruvic transaminase; GSH: glutathione; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; ROS: reactive oxygen species; SFTSV: severe fever with thrombocytopenia virus; SQSTM1/p62: sequestosome 1.

Fecal calprotectin (FC) is a biomarker of gut inflammation but its association with sepsis associated liver dysfunction (SALD) is unclear. This single-center, prospective cohort study investigated the relationship between FC and SALD in adults with sepsis. FC concentrations were measured on days 1 (FC1) and 3 (FC3). The difference between FC3 and FC1 (∆FC) was calculated. The relationship between FC and SALD was assessed using multivariate analysis. Receiver operating characteristic curves were used to assess the predictive value of SALD biomarkers. Ninety-five patients with sepsis (33 with SALD and 62 without SALD) were enrolled between January 2023 and March 2024. The median FC3 level and ∆FC were significantly higher in the SALD group than in the non-SALD group (both p < 0.001), whereas the median FC1 level did not differ significantly between groups. FC3 level and ∆FC were positively associated with SALD in the adjusted analysis (both p < 0.001) with areas under the curve of 0.784 and 0.848, respectively, and cut-off values of 930.88 μg/g and - 8.80 μg/g, respectively. In adults with sepsis, SALD occurrence was more strongly associated with elevated FC3 levels and ∆FC than with FC1 levels; therefore, monitoring FC3 levels and ∆FC could help detect SALD.

We investigated the effect of single-nucleotide polymorphisms (SNPs) in the high mobility group box 1 (HMGB1) gene on morbidity and mortality after liver transplantation (LT). Among 120 LT recipients and their living donors, the genotypes of HMGB1, and the SNPs rs2249825, rs1045411, rs1412125, and rs1360485 were determined. There were no significant associations between these four SNPs and the incidence of rejection or mortality. However, the incidence of early allograft dysfunction (EAD) (n = 43), which presents as functional insufficiency within 1 week of LT, was significantly higher in recipients with the GC + CC allele of rs2249825 (n = 17/34) than in those with the GG allele (n = 26/86) (p = 0.044). Although the impact of donor HMGB1 SNPs on the incidence of EAD was not statistically significant, recipients with the GC + CC allele of rs2249825 who received liver grafts from donors with the same genotype had the highest incidence of EAD (p = 0.052). In contrast, the donor TC + CC allele of rs1412125 was an independent risk factor for the development of sepsis (n = 33) in LT recipient (OR = 3.05, 95 % CI = 1.18-7.87, p = 0.021). Thus, the SNPs of the HMGB1 gene in either recipients or donors were not associated with mortality but influenced the incidence of EAD and sepsis, likely being a predictive biomarker for the risk of serious complications after LT.

Sepsis‑induced myopathy (SIM) is a common complication in intensive care units, which is often associated with adverse outcomes, primarily manifested as skeletal muscle weakness and atrophy. Currently, the management of SIM focuses on prevention strategies, as effective therapeutic options remain elusive. Glucagon‑like peptide‑1 (GLP‑1) receptor agonists (GLP‑1RAs) have garnered attention as hypoglycemic and weight‑loss agents, with an increasing body of research focusing on the extrapancreatic effects of GLP‑1. In preclinical settings, GLP‑1RAs exert protective effects against sepsis‑related multiple organ dysfunction through anti‑inflammatory and antioxidant mechanisms. Based on the existing research, we hypothesized that GLP‑1RAs may serve potential protective roles in the repair and regeneration of skeletal muscle affected by sepsis. The present review aimed to explore the relationship between GLP‑1RAs and sepsis, as well as their impact on muscle atrophy‑related myopathy. Furthermore, the potential mechanisms and therapeutic benefits of GLP‑1RAs are discussed in the context of muscle atrophy induced by sepsis.

Pediatric sepsis is a prevalent severe condition with a high disability rate and mortality. The purpose of this study was to investigate how NK cell-related genes (NKGs) function in the diagnosis of pediatric sepsis. Differential analysis and Venn analysis were utilized to screen differentially expressed NKGs (DE-NKGs) in pediatric sepsis. The PPI network of DE-NKGs was generated using STRING. Candidate drugs are predicted using the CMAP database. miRNA and transcription factor (TF) targeting hub genes were screened using the Networkanalyst website. A total of 22 DE-NKGs were identified, which were mainly enriched in immune-related biological processes. Ten hub genes that were filtered out from DE-NKGs exhibited good diagnostic performance. Immune infiltration analysis revealed that macrophages and neutrophils had higher infiltration abundance in the pediatric sepsis group, whereas NK cells had higher infiltration abundance in the normal group. NKGs (LCK, FCER1G, PRF1, CD247, GZMB, CD2, CCL4, KLRD1, CCL5, and ITGB2) with diagnostic performance were successfully predicted, and some potential miRNAs, TFs, and candidate drugs were also predicted. In conclusion, this study threw light on a comprehensive understanding of the role of NK cells in pediatric sepsis.

Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.

This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.

Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.

Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206+CD73+ M2-like macrophages and PDL1-CD39-CCR2+ neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP+NGP+CD177+ phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP+NGP+CD177+ neutrophils, altering intercellular communication within the septic liver immune microenvironment.

This study demonstrated TPPU's protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.

Macrophage pyroptosis represents a pivotal mechanism underlying acute liver injury during sepsis. Chloride intracellular channel proteins (CLICs) have been linked to inflammatory reflexes, with IAA94 serving as an inhibitor of channel formation characteristic of CLICs. In a mouse model, IAA94 demonstrated efficacy in reducing pro-inflammatory cytokines in liver tissues, decreasing macrophage in the liver, inhibiting the development of the pro-fibrosis phenotype, and alleviating tissue injury. Additionally, IAA94 exhibited inhibitory effects on the activation of NLRP3 inflammasome, leading to the suppression of pyroptosis in J774A.1 cells and the liver. Additionally, IAA94 was observed to impede the interaction between NEK7 and NLRP3. Furthermore, it was observed that the conditioned medium of pyroptotic macrophages treated with IAA94 induced an attenuated inflammatory response in hepatocytes in comparison to that induced by the conditioned medium of pyroptotic macrophages. However, NLRP3 overexpression impeded the beneficial effects of IAA94. In conclusion, IAA94 has the capacity to impede NLRP3 inflammasome formation-mediated pyroptosis by blocking CLICs-mediated chloride efflux and the inhibition of NEK7-NLRP3 interactions, thereby establishing CLICs as a promising therapeutic target against liver inflammation.

The severity of sepsis is attributed to excessive inflammatory responses leading to liver injury. Pregnane X receptor (PXR), a nuclear receptor that controls xenobiotic and endobiotic metabolism, has been implicated in regulating inflammation and liver regeneration. This study aimed to investigate the role of PXR in sepsis-induced liver injury and the underlying mechanisms. Sepsis models were established in mice, the mice were administered the typical mouse PXR agonist PCN (100 mg·kg-1·d-1, i.p.) for 3 consecutive days in advance, then subjected to CLP operation or LPS administration 1 h after the last administration of PCN. The results showed that PCN pretreatment significantly increased the survival rate of septic mice, while the survival rate was reduced after the knockout of Pxr. In addition, PCN pretreatment effectively alleviated sepsis-induced liver injury. In Pxr knockout mice, liver injury was more severe, whereas the protective effects of PCN pretreatment were abolished. Mechanistically, PCN pretreatment significantly upregulated the expression of yes-associated protein (YAP) and its downstream targets and decreased the level of phosphorylated nuclear factor-κB (NF-κB). Moreover, liver-specific knockdown of Yap blocked the protective effects of PCN pretreatment against sepsis-induced liver injury and downregulated the phosphorylation level of NF-κB. In summary, this study demonstrated that PXR activation protects against sepsis-induced liver injury through activation of the YAP signaling pathway, providing a new strategy for the diagnosis and treatment of sepsis-induced liver injury.

Macrophage apoptosis is a key contributor to the elimination of immune cells and increased susceptibility during sepsis. CKLF like MARVEL transmembrane domain containing 4 (CMTM4) is a membrane protein with four transmembrane domains. It has recently been implicated in the regulation of immune cell biological functions. However, its role in regulating macrophage apoptosis during sepsis has not been extensively studied.

Clinical samples were analyzed to determine CMTM4 expression levels and their correlation with clinical examination results. An in vitro model was developed using C57BL/6 mice and the THP-1 cell line. An immunofluorescence analysis was used to assess protein expression levels, apoptosis, and protein co-localization. Western blotting (WB) was used to measure protein expression levels, while flow cytometry was used to detect cell apoptosis. Transcriptomic sequencing was conducted to identify differentially expressed genes and to perform a functional enrichment analysis. Transcription factors were screened using databases. Chromatin immunoprecipitation, followed by quantitative PCR (ChIP-qPCR), was conducted to analyze protein-DNA interactions, and co-immunoprecipitation (Co-IP) was used to examine protein-protein interactions.

CMTM4 expression in macrophages was upregulated in sepsis. The inhibition of CMTM4 expression reduced macrophage apoptosis. PD-L1 was identified as a key molecule regulated by CMTM4 in macrophage apoptosis. CMTM4 regulates PD-L1 by promoting the phosphorylation of its transcription factor, STAT2, rather than directly binding to PD-L1.

In sepsis, CMTM4 facilitates PD-L1-dependent macrophage apoptosis by enhancing STAT2 phosphorylation. This discovery offers new insights for the diagnosis and treatment of sepsis.

Sepsis-associated liver injury (SALI) refers to secondary liver function impairment caused by sepsis, patients with SALI often have worse clinical outcomes. The early identification and assessment of the occurrence and progression of SALI are pressing issues that urgently need to be resolved.

To investigate the relationship between iron metabolism and SALI.

In this prospective study, 139 patients were recruited, with 53 assigned to the SALI group. The relationships between SALI and various iron metabolism-related biomarkers were examined. These biomarkers included serum iron (SI), total iron-binding capacity (TIBC), serum ferritin, transferrin, and transferrin saturation. To identify independent risk factors for SALI, both univariate and multivariate logistic regression analyses were performed. Additionally, receiver operating characteristic curve analysis was utilized to assess the predictive value of these biomarkers for the occurrence of SALI.

There were no statistically significant differences in age, sex, body mass index, Sequential Organ Failure Assessment scores (excluding liver function), or APACHE II scores between the two groups of patients. Compared with the sepsis group, the SALI group presented significantly higher SI (P < 0.001), TIBC (P < 0.001), serum ferritin (P = 0.001), transferrin (P = 0.005), and transferrin saturation levels (P < 0.001). Multivariate logistic regression analysis revealed that SI (odds ratio = 1.24, 95% confidence interval: 1.11-1.40, P < 0.001) and TIBC levels (odds ratio = 1.13, 95% confidence interval: 1.05-1.21, P < 0.001) were independent predictors of SALI. Receiver operating characteristic curve analysis revealed that SI and TIBC had areas under the curve of 0.816 and 0.757, respectively, indicating moderate predictive accuracy for SALI.

Iron metabolism disorders are closely associated with the development of SALI, and SI and TIBC may serve as potential predictive biomarkers. The combined use of SI and TIBC has superior diagnostic efficacy for SALI. These findings provide valuable insights for the early identification and management of SALI among patients with sepsis.

Group A Streptococcus (GAS) is a pathogen that is capable of colonizing various infection sites and can potentially elicit an inadequate immune response that will lead to sepsis. The processes underlying this misdirected immune reaction remain poorly understood, and reliable biomarkers for indicating impending organ failure during sepsis are still missing. The present study aims to identify parameters that can predict the onset of end-organ damage in the course of sepsis. To that extent, we investigated key aspects of the immune response in early-phase sepsis following infection of different tissues in a mouse model, using Brefeldin A to link cytokine production to specific cell types through multi-parameter flow cytometry. Subcutaneous and intravenous GAS infections resulted in clinical sepsis, which was paralleled by peripheral blood lymphopenia. Intravenous infection in particular was associated with a higher bacterial burden in the liver that strongly correlated with an increased granulocyte-to-lymphocyte ratio of the peripheral blood. Strikingly, IL-6 overexpression was more pronounced in intravenous infection and strongly correlated with hepatic stress, indicated by elevated bacterial loads in the liver. Collectively, our data highlight the potential utility of IL-6 in conjunction with an elevated granulocyte-to-lymphocyte ratio as promising early indicators of concomitant liver stress in sepsis.

Sepsis-related organ damage, as the most intractable problem in intensive care units (ICUs), receives a great deal of attention from healthcare professionals. Sepsis-associated liver injury (SALI) often leads to poor clinical outcomes due to its complex physiological mechanism. In previous studies, chemokine receptor 5 (CCR5) inhibitors were shown to exert unique anti-inflammatory effects. As the therapeutic effect of maraviroc (MVC) on SALI is still unclear, we aimed to explore whether MVC is effective in treating SALI. We established a model of SALI by cecal ligation and puncture (CLP) and intraperitoneally injected 20 mg/kg MVC 2 h after CLP. The results showed that MVC could significantly ameliorate liver injury after CLP. Furthermore, we demonstrated that MVC reduced inflammatory infiltration and apoptosis after SALI. In addition, we found that the function of MVC in reducing inflammation was obtained through the inhibition of the two inflammatory signaling pathways mentioned above. Finally, the JNK agonist AN was chosen for reverse research. As shown by the results, the therapeutic effects of MVC disappeared after AN treatment, indicating that MVC exerted anti-inflammatory and antiapoptotic effects through JNK. Our study revealed that MVC could reduce liver injury after SALI by inhibiting liver inflammation and hepatocyte apoptosis induced by CLP and that MVC exerted diminish inflammatory effects by inhibiting the NF-κB and MAPK signaling pathways.

Our aim was to explore the IL-27 effect in sepsis (SP)-related acute hepatic injury (AHI) as well as its possible mechanism.

Herein, we utilized both wild-type (WT) and IL-27 receptor (WSX-1)-deficient (IL-27R-/-) mice alongside RAW264.7 cells. Our study established an SP-associated AHI model through the intraperitoneal injections of lipopolysaccharide (LPS) + D-galactosamine (D-G). For examining the IL-27 impact on AHI, mice serum and liver tissue samples were gathered. Inflammatory factor levels in the liver and serum were detected using ELISA and immunohistochemistry. Immunofluorescence and Western blot techniques were employed for the detection of protein expression associated with polarization and pyroptosis in the liver, including iNOS, ARG-1, caspase-11, RAGE, and GSDMD. To further verify the IL-27 effects on macrophage polarization and pyroptosis and explore possible mechanisms involved, we used LPS-triggered RAW264.7 macrophages to assess AMPK/SIRT1 expression after IL-27 intervention. This study utilized Compound C (CC) to block the AMPK/SIRT1 pathway. The inflammatory response level and protein expression related to macrophage polarization and pyroptosis were measured again to reveal IL-27 implication in AHI and determine whether its role is associated with the AMPK/SIRT1 pathway.

The results revealed that IL-27 exacerbated systemic inflammation and liver damage in AHI mice by promoting M1 macrophage polarization, thereby increasing pro-inflammatory phenotype macrophages (M1). This further exacerbated the inflammatory response and pyroptosis in vivo and in vitro. Additionally, IL-27 down-regulated p-AMPK and SIRT1 protein expression while overexpressing macrophage inflammatory mediators including IL-1β/6 and TNFα. Furthermore, IL-27 promoted increased RAGE and caspase-11 protein expression, aggravating macrophage pyroptosis. Employing CC to block the AMPK pathway further aggravated M1 macrophage polarization and pyroptosis in vitro and in vivo, ultimately worsening liver injury.

Here, IL-27 aggravates AHI by promoting macrophage M1 polarization to induce caspase-11-mediated pyroptosis in vitro and in vivo, which may be linked to the AMPK/SIRT1 signaling pathway.

Sepsis is defined as a condition related to infection that manifests with multiorgan dysfunction, representing a life-threatening state. Consequently, severe complications frequently occur, with liver injury being one of the most prevalent serious complications of sepsis. Liver dysfunction during sepsis serves as an independent predictor of mortality. This review provides a comprehensive overview of current research on sepsis-induced liver injury (SILI), encompassing the clinical manifestations, diagnostic criteria, pathogenesis and therapeutic strategies associated with this condition. SILI may manifest as hypoxic hepatitis due to ischemia and shock, cholestasis resulting from abnormal bile metabolism, or bile duct sclerosis. The pathophysiology of sepsis involves intricate interactions among the inflammatory response, oxidative stress, and cell death. All of these factors complicate treatment and represent potential targets for therapeutic intervention. Furthermore, this review addresses the limitations inherent in conventional therapies currently employed for managing SILI and emphasizes the potential of novel targeted strategies aimed at addressing the fundamental mechanisms underlying this condition.

Sepsis-induced liver injury (SILI) is a severe complication of sepsis. Wedelolactone (WEL) can be used to treat liver diseases. However, its therapeutic mechanisms and efficacy in SILI remain unclear. To investigate the therapeutic effects of WEL on SILI and its potential mechanisms of action through in vitro and in vivo experiments.

A SILI model based on lipopolysaccharide (LPS), and AML12 cells were treated with different concentrations of WEL, LY294002 and ML385. The SILI model was established by caecal ligation and puncture (CLP). C57BL/6 mice were administered WEL and biphenyl diester for seven consecutive days, and CLP was then performed 1 h later. Blood and liver tissue were collected 24 h later for subsequent analysis. HE staining, liver function index, oxidative stress index, JC-1 staining, transmission electron microscopy, immunofluorescence staining, Western blot, and inflammatory cytokines were used to detect oxidative stress and ferroptosis-related markers.

The in vivo experiments showed that WEL treatment reduced the pathological damage of the liver and decreased ALT and AST, MMP and ROS (the product of iron and lipid peroxidation) and inflammatory factors. WEL also decreased hepatocyte viability in vitro. Inhibition of NRF2 can lead to exacerbation of SILI. The expressions of P-PI3K and P-AKT were up-regulated while HO-1, GPX4, NRF2, and SLC7A11 were down-regulated in vitro and in vivo.

Ferroptosis and oxidative stress are pivotal in SILI. WEL mitigates SILI by inhibiting ferroptosis and oxidative stress, primarily through the PI3K/AKT/NRF2 and SLC7A11/GPX4 signalling pathways, thus suggesting a promising therapeutic strategy.

The 2024 revised edition of the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock (J-SSCG 2024) is published by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. This is the fourth revision since the first edition was published in 2012. The purpose of the guidelines is to assist healthcare providers in making appropriate decisions in the treatment of sepsis and septic shock, leading to improved patient outcomes. We aimed to create guidelines that are easy to understand and use for physicians who recognize sepsis and provide initial management, specialized physicians who take over the treatment, and multidisciplinary healthcare providers, including nurses, physical therapists, clinical engineers, and pharmacists. The J-SSCG 2024 covers the following nine areas: diagnosis of sepsis and source control, antimicrobial therapy, initial resuscitation, blood purification, disseminated intravascular coagulation, adjunctive therapy, post-intensive care syndrome, patient and family care, and pediatrics. In these areas, we extracted 78 important clinical issues. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 42 GRADE-based recommendations, 7 good practice statements, and 22 information-to-background questions were created as responses to clinical questions. We also described 12 future research questions.

Andrographolide (AP) has been shown to possess anti-inflammatory activities. In this study, the impact of AP in sepsis-induced acute liver injury (ALI) and the molecules involved were dissected. FKBP1A was predicted to be the sole target protein of AP that was also differentially expressed in the GSE166868 dataset. AP induced the protein expression of FKBP1A and suppressed that of NOTCH1 in a dose-dependent manner. AP ameliorated ALI in mice induced by D-galactosamine and LPS and inhibited LPS-induced liver parenchymal cell injury in vitro. By contrast, the protective effect of AP was significantly lost after the knockdown of FKBP1A. As a positive control, the therapeutic effect of dexamethasone on ALI may be related to NOTCH1, which was not related to FKBP1A. NOTCH1 promoted AK2 transcription in liver parenchymal cells, and FKBP1A inhibited endoplasmic reticulum (ER) stress by impairing NOTCH1/AK2 signaling. Restoration of NOTCH1 significantly reversed the hepatoprotective effect of AP in ALI mice and LPS-induced liver parenchymal cell injury by activating the ER stress pathway. Therefore, AP-promoted FKBP1A expression inhibits ALI progression by blocking the NOTCH1/AK2-mediated ER pathway.

Sepsis-associated liver injury (SALI) is a common complication in sepsis patients, significantly affecting their prognosis. Previous studies have shown that aspirin can improve the prognosis of septic patients. However, there is currently a lack of clinical evidence supporting the use of aspirin in the treatment of SALI. Therefore, we conducted this study to explore the association between the use of aspirin and the prognosis of patients with SALI.

The patients in this study were obtained from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, version 3.0. The primary outcome was 30-day all-cause mortality. Baseline characteristics between the aspirin and non-aspirin groups were balanced using propensity score matching (PSM). The Kaplan-Meier survival curve and Cox regression analysis were used to investigate the association between aspirin use and the prognosis of patients with SALI.

Of 657 SALI patients in this study, 447 (68%) patients had not used aspirin during hospitalization, whereas 210 (32%) had. After PSM, the 30-day mortality was 33.1% in the non-aspirin group and 21% in the aspirin group, indicating a significantly reduced mortality risk in the aspirin group (HR, 0.57; 95% CI, 0.37-0.90; P = 0.016). Similarly, the results of the multivariable Cox regression analysis and inverse probability weighting (IPW) analysis showed that, compared to the non-aspirin group, the aspirin group had a significantly lower 30-day mortality risk (Multivariable Cox regression analysis: HR, 0.69; 95% CI, 0.48-0.99; P = 0.047; IPW: HR, 0.62; 95% CI, 0.43-0.89; P = 0.010).

Aspirin can reduce 30-day mortality in SALI patients, regardless of the dose or timing of administration. However, careful assessment based on individual differences is essential to ensure the safety and effectiveness of aspirin use.

Sepsis, a systemic immune syndrome caused by severe trauma or infection, poses a substantial threat to the health of patients worldwide. The progression of sepsis is heavily influenced by septic liver injury, which is triggered by infection and cytokine storms, and has a significant impact on the tolerance and prognosis of septic patients. The objective of our study is to elucidate the biological role and molecular mechanism of fibroblast growth factor 21 (FGF21) in the process of sepsis.

This study was undertaken in an attempt to elucidate the function and molecular mechanism of FGF21 in therapy of sepsis.

Serum concentrations of FGF21 were measured in sepsis patients and septic mice. Liver injury was compared between mice FGF21 knockout (KO) mice and wildtype (WT) mice. To assess the therapeutic potential, recombinant human FGF21 was administered to septic mice. Furthermore, the molecular mechanism of FGF21 was investigated in mice with myeloid-cell specific HIF-1α overexpression mice (LyzM-CreDIO-HIF-1α) and myeloid-cell specific Atg7 knockout mice (Atg7△mye).

Serum level of FGF21 was significantly increased in sepsis patients and septic mice. Through the use of recombinant human FGF21 (rhFGF21) and FGF21 KO mice, we found that FGF21 mitigated septic liver injury by inhibiting the initiation and propagation of inflammation. Treatment with rhFGF21 effectively suppressed the activation of proinflammatory macrophages by promoting macroautophagy/autophagy degradation of hypoxia-inducible factor-1α (HIF-1α). Importantly, the therapeutic effect of rhFGF21 against septic liver injury was nullified in LyzM-CreDIO-HIF-1α mice and Atg7△mye mice.

Our findings demonstrate that FGF21 considerably suppresses inflammation upon septic liver injury through the autophagy/ HIF-1α axis.