Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and remains a leading cause of death worldwide. Hyperlactatemia, a hallmark metabolic disorder in sepsis, has recently been recognized as an epigenetic modulator via lysine lactylation. This Review synthesizes the evolving understanding of lactate-from a prognostic biomarker to a pathogenic mediator and, most recently, to an epigenetic modulator through lysine lactylation (Kla). Sepsis induces persistent Warburg-like glycolytic reprogramming in immune and parenchymal cells, generating lactate that not only serves as a metabolic fuel but also accumulates to drive covalent histone and non-histone Kla. Rather than merely indicating tissue hypoxia, this lactate surge directly remodels transcriptional and metabolic programs via both lactyl-CoA-dependent (p300/CBP, KAT2B) and lactyl-CoA-independent (AARS1/2) lactylation pathways. We dissect the emerging regulatory network of Kla in sepsis, including validated "writers" and "erasers", as well as potential writers and erasers awaiting validation in sepsis models, and map their cell type-specific and substrate-specific effects on acute lung injury, cardiomyopathy, acute kidney injury, and vascular dysfunction. The identical lactylation mark-exemplified by H3K18la-exhibits a context-dependent duality, being protective in macrophages yet pathogenic in alveolar or tubular epithelia. This complexity underscores the urgent need for precision-oriented therapeutic strategies. We further explore how lactate and Kla shape the immunopathological landscape of sepsis by modulating macrophage polarization, trained immunity, neutrophil extracellular trap (NET) formation, and T-cell dysfunction, and we compare these effects with the relatively more uniform immunosuppressive role of lactylation in cancer. Finally, we map the currently known landscape of both histone and non-histone Kla across the various stages of sepsis, thereby providing new avenues for mechanism-based therapies in sepsis and other inflammation-associated disorders.

BackgroundSepsis-induced immunosuppression, characterized by dendritic cell (DC) depletion, correlates with poor outcomes. The glycoprotein FSTL1 is elevated in sepsis, but its contribution to DC pyroptosis and subsequent immune dysfunction remains unknown.MethodsWe utilized in vitro models with splenic DCs and mouse dendritic cell line DC2.4, alongside a murine cecal ligation and puncture (cecal ligation and puncture) sepsis model. The roles of STING and autophagy were probed using specific modulators (STING agonist DMXAA; STING specific inhibitor C-176; autophagy inhibitor 3-methyladenine). Pyroptosis was assessed by quantifying cleaved CASP1 and GSDMD-N via Western blotting and flow cytometry. STING pathway activation and autophagic flux were evaluated by detecting protein phosphorylation (p-STING, p-TBK1) and key markers (LC3B, P62) through Western blotting, immunofluorescence, and co-immunoprecipitation. DC-mediated T-cell responses were determined by proliferation assays and cytokine secretion analysis.ResultsFSTL1 was found elevated and correlated withDC pyroptosis in vitro and in septic mice. Mechanistically, FSTL1 inhibited the autophagic degradation of STING, leading to its accumulation and subsequent activation. Consequently, this impaired T-cell priming capacity and resulted in immunosuppression in vivo. Inhibition of STING attenuated FSTL1-induced pyroptosis, restored DC-mediated T-cell activation, and ameliorated immunosuppression. In murine septic models, FSTL1 exacerbated multiple organ injury and increased mortality, effects that were reversed by STING inhibition.ConclusionOur findings demonstrate that FSTL1 correlates with impaired STING autophagic degradation and DC pyroptosis, suggesting a potential pathway contributing to septic immune dysfunction.

The gut microbiota plays a critical regulatory role in the pathogenesis of sepsis, yet the immunomodulatory mechanisms of Limosilactobacillus reuteri (L. reuteri) and its metabolites in sepsis remain to be fully elucidated. This study found that the abundance of intestinal L. reuteri was significantly reduced in patients with bacterial sepsis and showed a negative correlation with disease severity. In a mouse model of sepsis induced by cecal ligation and puncture, fecal microbiota transplantation and live bacterial supplementation further confirmed that live L. reuteri effectively attenuated sepsis progression. Integrated metabolomic and network pharmacological analysis identified indole-3-carboxaldehyde (IAld), a metabolite derived from L. reuteri, which enhances macrophage bactericidal function and alleviates sepsis-associated organ damage. Mechanistically, IAld directly targets DUSP1 in macrophages, inhibits its phosphatase activity, thereby promoting ERK phosphorylation, upregulating NOX2 expression, stimulating reactive oxygen species production, and ultimately enhancing bacterial clearance. Notably, circulating IAld levels in septic patients were significantly inversely correlated with SOFA score, APACHE II score, and arterial lactate levels, and IAld safely enhanced the bactericidal function of human macrophages in vitro. This study is the first to systematically demonstrate that L. reuteri and its metabolite IAld exert a protective effect against sepsis through the DUSP1/ERK/NOX2/ROS axis, providing novel mechanistic insights and potential therapeutic targets for immunometabolic intervention in sepsis.

OBJECTIVE:To evaluate whether serial diaphragmatic excursion (DE) and diaphragmatic thickening fraction (DTF) are associated with subsequent tracheal intubation during high-flow nasal cannula (HFNC) therapy and whether they add information beyond the ROX index. DESIGN:Prospective, single-center, repeated-measures cohort study. SETTING:Intensive care unit. PATIENTS:Consecutive adults with acute hypoxemic respiratory failure receiving HFNC. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Right-sided diaphragm ultrasound was performed at HFNC initiation and 1, 3, 6, 9, and 12 h. The primary outcome was intubation within 48 h of HFNC initiation. At T1-T5 landmarks, current DE, DTF, and ROX were used to estimate remaining intubation risk through 48 h using pooled logistic regression with patient-clustered robust standard errors. Next-window prediction was a sensitivity analysis. Among 270 patients, 64 (23.7%) were intubated; 1491 ultrasound assessments yielded 1221 person-period records. After adjustment for age and APACHE II, each 1-SD increase in DTF (35.7 percentage points) was associated with higher intubation odds (OR, 1.50; 95% CI, 1.29-1.74; P < 0.001), whereas DE was not. ROX remained the stronger bedside marker. Adding DTF to ROX improved apparent AUC from 0.707 to 0.736 (delta AUC, 0.029; cluster-bootstrap 95% CI, 0.009-0.055); adding DE provided little improvement. Next-window results were directionally consistent. CONCLUSIONS:Serially measured DTF, but not DE, was associated with subsequent intubation risk. DTF may complement, but should not replace, ROX and clinical assessment.

Previous studies have shown that SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1) provides protective effects against lipopolysaccharide (LPS)-induced acute lung injury (ALI), however the underlying mechanism remains unclear. A recent study highlighted SIGMAR1's protective role against ferroptosis but did not fully elucidate the mechanism involved. Endothelial ferroptosis, which significantly affects microvascular permeability, has garnered increasing attention in research. In this context, we aimed to investigate how SIGMAR1 mitigates endothelial ferroptosis in ALI induced by LPS. PRE-084 (SIGMAR1 activator) inhibited endothelial ferroptosis and microvascular hyperpermeability in ALI induced by LPS; however, this effect was blocked by mitophagy inhibition. Knockout of sigmar1 worsened microvascular hyperpermeability and endothelial ferroptosis, but these effects were mitigated by activating SIRT3 (sirtuin 3). Conversely, inhibiting SIRT3 blocked the upregulation of SIGMAR1-mediated mitophagy and limited endothelial ferroptosis in ALI induced by LPS. In addition, LPS exposure led to the acetylation of lysine 498 in ATP5F1A/ATP5A1 (ATP synthase F1 subunit alpha). Importantly, downregulating ATP5F1A acetylation prevented the SIRT3 inhibition from blocking the effects of SIGMAR1 in facilitating mitophagy and preventing ferroptosis. Interestingly, downregulating ATP5F1A acetylation or activation of SIRT3 did not alter the effects of PRE-084 on ALI when mitophagy was inhibited, suggesting that SIGMAR1's ALI protective effects involve ATP5F1A- or SIRT3-dependent mitophagy. In conclusion, our findings indicate that SIGMAR1 alleviates endothelial ferroptosis and microvascular hyperpermeability in LPS-induced ALI through SIRT3-mediated mitophagy. Furthermore, the deacetylation of ATP5F1A at lysine 498 by SIRT3 is essential for SIGMAR1-mediated PRKN/parkin-dependent mitophagy.Abbreviations: ALI, acute lung injury; ARDS, acute respiratory distress syndrome; ATP, adenosine triphosphate; ATP5F1A, ATP synthase F1 subunit alpha; BCA, bicinchoninic acid; EB, Evans blue dye; ECM, endothelial cell medium; FBS, fetal bovine serum; FITC, fluorescein isothiocyanate; Fer-1, ferrostatin-1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP-LC3, green fluorescent protein-microtubule associated protein 1 light chain 3 alpha; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; KO, knockout; LPS, lipopolysaccharide; LRRK2, leucine rich repeat kinase 2; MDA, malondialdehyde; MPMVECs, mouse pulmonary microvascular endothelial cells; MTT, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; PECAM1/CD31, platelet and endothelial cell adhesion molecule 1; PRKN, parkin RBR E3 uniquitin protein ligase; ROS, reactive oxygen species; RSL3, RAS-selective lethal 3; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SIGMAR1, sigma non-opioid intracellular receptor 1; SIRT3, sirtuin 3; siRNA, small interfering RNA; TUNEL, terminal deoxyribonucleotidyl transferase-mediated deoxyuridine 5-triphosphate-digoxigenin nick end labeling; VHP, vascular hyperpermeability; W:D, wet:dry; WT, wild type.

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 Tmed9 prevented the activation of STING1 and GSDME-mediated pyroptosis by disturbing ERGIC structure. These results suggest a novel RETREG1-based protective mechanism against DC-mediated immune impairment during sepsis. Genetic or pharmacological modulation of RETREG1 May represent a promising therapeutic strategy for treating sepsis-induced immune suppression.Abbreviations: 7-AAD: 7-aminoactinomycin D; ANXA5/annexin V: annexin A5; ARF1: ARF GTPase 1; ATP: adenosine triphosphate; CALCOCO1: calcium binding and coiled-coil domain 1; CASP1: caspase 1; cC3: cleaved CASP3; CCDC50: coiled-coil domain containing 50; CD274/PD-L1: CD274 molecule; CFSE: carboxyfluorescein diacetate succinimidyl ester; CGAS: cyclic GMP-AMP synthase; CLP: cecal ligation and puncture; DC: dendritic cell; DEGs: differentially expressed genes; DEPs: differently expressed proteins; ER: endoplasmic reticulum; ERGIC: endoplasmic reticulum-Golgi intermediate compartment; GO: Gene Ontology; GOLGA2/GM130: golgin A2; GSDMD: gasdermin D; GSDME: gasdermin E; GSEA: Gene set enrichment analysis; IFN-I: type I interferon; IKK: IκB kinase; IL2: interleukin 2; IRF3: interferon regulatory factor 3; ITGAX/Cd11c: integrin subunit alpha X; KEGG: Kyoto Encyclopedia of Genes and Genomes; LMAN1/ERGIC53: lectin, mannose binding 1; LPS: lipopolysaccharide; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; NFKB/NFκB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; PBMCs: peripheral blood mononuclear cells; PBS: phosphate-buffered saline; PCD: programmed cell death; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; PRRs: pattern recognition receptors; PYCARD/ASC: PYD and CARD domain containing; RETREG1/FAM134B: reticulophagy regulator 1; SAMHD1: SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1; SEC62: SEC62 preprotein translocation factor; SQSTM1/p62: sequestosome 1; STEEP1: STING1 ER exit protein 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TGFB/TGFβ: transforming growth factor beta; TMED9: transmembrane p24 trafficking protein 9; TLR4: toll like receptor 4; TNF: tumor necrosis factor; Tregs: regulatory T cells; VAP: VAMP associated protein.

Abstract Objective: Previously, we demonstrated that polydatin (PD) protected against acute lung injury (ALI) by upregulation of mitophagy; however, the mechanism remains unclear. In the present study, we aimed to determine whether PD facilitates mitophagy by downregulating p53 and then alleviates ferroptosis in ALI. Materials and Methods: Lipopolysaccharide (LPS) was administered intratracheally to the mice to induce ALI. ALI was induced by stimulating mouse lung epithelial cell line-12 (MLE-12) cells with 5 μg/mL LPS for 12 h in vitro . Results: We found that the downregulation of mitophagy by silencing Prkn (Parkin) exacerbated LPS-induced ferroptosis, suggesting the protective effect of Parkin-dependent mitophagy prevents LPS-induced ferroptosis. Furthermore, PD treatment alleviated LPS-induced ferroptosis; however, the protective effect of PD was attenuated by mitophagy inhibition. We previously reported that p53 promotes ferroptosis in ALI via an as-yet-unknown mechanism. Herein, p53 was observed to interact with Parkin to prevent its translocation into mitochondria, thereby decreasing mitophagy in ALI. Moreover, upregulating p53 exacerbated LPS-induced ferroptosis, which was rescued by upregulation of mitophagy, indicating that p53 facilitates ferroptosis by depressing mitophagy. In the present study, we found that PD treatment prevented LPS-induced upregulation of p53. Moreover, overexpression of p53 inhibited PD-mediated upregulation of mitophagy and its protective effect against ferroptosis. Interestingly, upregulation of mitophagy rescued the reduced protective effect of PD against ferroptosis due to overexpression of p53. Conclusions: This study reveals that PD treatment prevents LPS-induced ferroptosis by upregulation of Parkin-dependent mitophagy in ALI. Additionally, p53 interacts with Parkin to facilitate ferroptosis by depressing mitophagy. We further found that PD enhances Parkin-dependent mitophagy by downregulating p53.

ObjectiveAcute Pancreatitis (AP) is a common acute abdominal disease in clinical practice. The gut microbiome is recognized as a key regulator in the development of acute pancreatitis. Akkermansia muciniphila (AKK) is recognized as a functional probiotic strain and has a beneficial effect on the progression of many diseases. However, the role of the AKK in the development of AP remains unclear. Here, we evaluated the potential contribution of AKK to AP.DesignRelative abundance of gut microbial AKK in AP was evaluated. A rat model of acute pancreatitis was established by retrograde pancreatic duct infusion of sodium taurocholate. Non-targeted and targeted metabolomics analysis were used for metabolites analysis.ResultsWe first found that the relative abundance of gut microbial AKK in AP patients was significantly reduced compared with that in healthy subjects. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably alleviates AP-related intestinal injury in AP rat models. Metabolomics studies found that the live AKK was able to generate Indole-3-lactic acid (ILA). ILA exerted a protective effect against AP-related intestinal injury, and significantly reduce inflammatory cell activation and pro-inflammatory factor overproduction. The mechanistic study revealed that ILA inhibits the apoptosis of intestinal epithelial cells by suppressing the activity of CASP3, and improves the role of intestinal barrier dysfunction in the AP model.ConclusionWe revealed that ILA, derived from live AKK, may act as a novel endogenous agonist for CASP3. ILA may serve as a new potential treatment method for intestinal injury in AP after successfully translating its efficacy into clinical practice.

BACKGROUND:The optimal glucose control strategy for intensive care unit (ICU) patients with diabetes remains a topic of debate. This study aimed to compare the effects of strict glucose control, intermediate strict glucose control, liberal glucose control, and very liberal glucose control on reducing all-cause mortality in ICU patients with diabetes through a network meta-analysis. METHODS:We conducted a search in PubMed, Cochrane Library, Embase, and Web of Science for randomized controlled trials comparing different glucose control strategies in ICU patients with diabetes up to October 1, 2024. The primary outcome was all-cause 90-day mortality. The Risk of Bias 2 tool was used to assess bias in the included studies. Data analysis was performed using Stata (version 17). RESULTS:A total of 12 randomized controlled trials involving 5,297 participants were included in the final analysis. The results showed that there was no statistically significant difference between the four glucose control strategies in reducing all-cause 90-day mortality. The surface under the cumulative ranking (SUCRA), which was used to rank the strategies and display the probability of each strategy being ranked first, showed the following: intermediate strict control (SUCRA 88%), liberal control (SUCRA 55.3%), very liberal control (SUCRA 40.3%), and strict control (SUCRA 16.5%). The cumulative probability of each strategy's rank in reducing all-cause mortality, from best to worst, showed that the most likely ranking was intermediate strict control, liberal control, very liberal control, and strict control. CONCLUSIONS:In ICU patients with diabetes, no significant statistical difference was observed among the four glucose control strategies in reducing all-cause 90-day mortality. The SUCRA rankings are hypothesis-generating and require further validation. Therefore, the current evidence is insufficient to definitively conclude that any one strategy is superior to the others in reducing mortality.

BackgroundDysregulated alterations in organelle structure and function have a significant connection with cell death, as well as the occurrence and development of inflammatory diseases. Maintaining cell viability and inhibiting the release of inflammatory cytokines are essential measures to treat inflammatory diseases. Recently, many studies have showed that autophagy selectively targets dysfunctional organelles, thereby sustaining the functional stability of organelles, alleviating the release of multiple cytokines, and maintaining organismal homeostasis. Organellophagy dysfunction is critically engaged in different kinds of cell death and inflammatory diseases.Aim of reviewWe summarized the current knowledge of organellophagy (e.g., mitophagy, reticulophagy, golgiphagy, lysophagy, pexophagy, nucleophagy, and ribophagy) and the underlying mechanisms by which organellophagy regulates cell death.Key scientific concepts of reviewWe outlined the potential role of organellophagy in the modulation of cell fate during the inflammatory response to develop an intervention strategy for the organelle quality control in inflammatory diseases.

Mitochondrial DNA (mtDNA) reportedly has diagnostic and predictive value in critically ill patients. This study evaluated the diagnostic and predictive value of mtDNA in patients undergoing continuous venovenous haemofiltration (CVVH). We consecutively enrolled 41 patients who were treated with CVVH from September 2018 to December 2019. Prefilter, postfilter, and ultrafiltrate samples were collected before the initiation of CVVH (T0) and 6 and 12 h after CVVH. The total mass removal rate (Mtr), total mass adsorption rate (Mad), plasma clearance (PC), and sieving coefficient (SC) were calculated based on the mass conservation principle. The plasma mtDNA concentration in patients at T0 prefilter was higher than that in healthy volunteers [13.77 (12.45–15.86) vs. 1.24 (1.15–1.34) ng/mL, P < 0.001]. Prefilter, but not postfilter or ultrafiltrate, mtDNA decreased during CVVH (P = 0.02), with a total CVVH clearance of 25.9

BackgroundThe lactate to hematocrit ratio (LHR) has not been assessed for predicting all-cause death in sepsis patients. This study aims to evaluate the relationship between LHR and 30-day all-cause mortality in sepsis patients.MethodsThis retrospective study used the data from Medical information mart for intensive care IV (MIMIC-IV, version 2.0). Our study focused on adult sepsis patients who were initially hospitalized in the Intensive care unit (ICU). The prognostic significance of admission LHR for 30-day all-cause mortality was evaluated using a multivariate Cox regression model, ROC curve analysis, Kaplan–Meier curves, and subgroup analyses.ResultsA total of 3,829 sepsis patients participated in this study. Among the cohort, 8.5% of individuals died within of 30 days (p < 0.001). The area under the curve (AUC) for LHR was 74.50% (95% CI: 71.6–77.50%), higher than arterial blood lactate (AUC = 71.30%), hematocrit (AUC = 64.80%), and shows no significant disadvantage compared to qSOFA, SOFA, and SAPS II. We further evaluated combining LHR with qSOFA score to predict mortality in sepsis patients, which shows more clinical significance. ROC curve analysis showed that 6.538 was the optimal cutoff value for survival and non-survival groups. With LHR ≥6.538 vs. LHR <6.538 (p < 0.001). Subgroup analysis showed significant interactions between LHR, age, sex, and simultaneous acute respiratory failure (p = 0.001–0.005).ConclusionLHR is an independent predictor of all-cause mortality in sepsis patients after admission, with superior predictive ability compared to blood lactate or hematocrit alone.

[This corrects the article DOI: 10.3389/fimmu.2023.1152186.].

目的 探讨硫酸多黏菌素B治疗耐碳青霉烯类革兰阴性菌(CR-GNB)脓毒症患者的临床疗效及安全性.方法 回顾性分析 2018 年 10 月—2022 年 1 月郴州医院收治的 93 例以硫酸多黏菌素B为基础的联合抗感染方案治疗CR-GNB脓毒症患者的临床资料.收集患者临床特征、细菌培养及药敏结果、抗菌药物种类及疗程、感染指标、临床疗效、不良反应、住院病死率等.结果 93例CR-GNB脓毒症患者中,感染部位以肺部为主(占65.6%);病原菌以鲍曼不动杆菌和肺炎克雷伯菌为主(分别占58.3%和25.2%).经硫酸多黏菌素B联合治疗后,有效率为79.6%(74/93),患者细菌清除率为68.8%(64/93),28 d全因死亡率为36.6%(34/93),90 d全因死亡率为52.7%(49/93).多黏菌素B使用时间越长,治疗有效率和细菌清除率越高,3～5 d、6～10 d、11～15 d、＞15 d 组治疗有效率分别为62.1%(18/29)、84.4%(38/45)、93.3%(14/15)、100%(4/4),χ2=7.415,P=0.045;细菌清除率分别为 48.3%(14/29)、80.0%(36/45)、73.3%(11/15)、75.0%(3/4),χ2=8.205,P=0.035.不同剂量的比较,治疗有效率(χ2=3.578,P=0.292)及细菌清除率(χ2=0.332,P=1.000)差异无统计学意义.多黏菌素B用药后疾病严重程度评分(APACHE Ⅱ评分和SOFA评分)、白细胞计数、血小板计数、尿素氮各时间点差异具有统计学意义(P＜0.05).结论 以硫酸多黏菌素B为基础的联合用药方案是CR-GNB脓毒症患者的有效选择.

Sepsis-induced inflammatory damage and adaptive repair are critical in the pathophysiological mechanisms of acute kidney injury (AKI). Here, we investigated the role of interferon regulatory factor three (IRF3) and subsequent activation of the Hippo pathway in inflammatory damage and repair using an in vitro cell model of LPS-induced AKI. LPS caused the phosphorylation and activation of IRF3 in the early stages of sepsis, and activated IRF3 enhanced the production of type I interferon (IFN), resulting in an excessive inflammatory response. Furthermore, LPS generated considerably more inflammatory injury than intended cell death, and IRF3 activation triggered the Hippo pathway, causing a reduction in YAP, which eventually impaired proliferation and repair in surviving renal tubular epithelial cells and exacerbated the development of AKI. In conclusion, IRF3 promoted the development of sepsis-associated AKI (SAKI) by modulating the Hippo pathway.

The stimulator of interferon genes (STING) is an adaptor protein involved in the innate immune response to the bacterial product cyclic dinucleotides (CDNs) or host DNA. The activation of STING pathway initiates interferon regulatory factor 3 (IRF3) and nuclear factor-KB (NF-KB). IRF3 can translocate to the nucleus and trigger the expression of immune stimulated genes (ISGs) and type I IFNs, leading to activation and migration of immune cells to the target cells, and NF-KB can drive the production of inflammatory cytokines. Thus, the activation of STING pathway may bridge innate and adaptive immunity. Autophagy, as an important part of cellular metabolism, is like a "smart recycling bin" in the human body, degrading abnormal and redundant substances and providing materials for the synthesis of new molecules to assist in maintaining homeostasis. Both STING and autophagy play a vital role in cellular, tissue, and organismal homeostasis. Due to the importance of STING and autophagy in maintaining cell survival and functional homeostasis, an increasing number of studies confirm that they are closely linked with each other. There are two main aspects: one is the regulation of autophagy key proteins by STING-dependent signaling network, the other is the regulation of autophagy on distinct links of STING activation pathway. Moreover, aberrant activation of STING or autophagic dysfunction, is critically involved in the pathogenesis of various illnesses, and more in-depth research has found that they jointly participate in the occurrence and development of diseases. This review will summarize the latest research on the mechanism of STING signaling and autophagy interaction and related human diseases, which may shed new light on the prevention and treatment of various diseases.

Background: The elevated plasma mitochondrial DNA (mtDNA) is associated with prognosis in patients with severe acute pancreatitis (SAP). However, it is not clear that the dynamic process of plasma mtDNA during the early stage of SAP and the correction between mtDNA and clinical features. Methods: Twenty-six eligible patients with SAP in the general intensive care unit of our institution were enrolled in this study. The mtDNA concentration were assessed at admission and on days 3, 5, and 7. Results: The mtDNA concentration of the patients with SAP was elevated at each time point compared with that in the healthy controls. The mtDNA levels increased rapidly, peaking on day 3 after admission, and began to decrease on day 5. The trend remained statistically consistent among the acute physiology and chronic health evaluation (APACHE II) score, the sequential organ failure assessment (SOFA) score, C-reactive protein (CRP) levels and mtDNA levels. Contrastingly, the changes were not statistically consistent among the procalcitonin (PCT), calciumion (Ca 2+ ) and mtDNA concentrations. The mtDNA level correlated significantly with the APACHE II score, SOFA score, and Ranson score, but not with the CRP, PCT, and Ca 2+ concentrations. Conclusions: The dynamic change of plasma mtDNA correlated significantly with SAP development. The elevated mtDNA levels could be used as a biomarker for the early stage of SAP. Trial registration: NCT: 04079777. Registered 4 September 2019 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S00096E5&selectaction=Edit&uid=U0002O5I&ts=2&cx=-e6bci8