Major depressive disorder (MDD) is pathologically associated with inflammatory-immune dysregulation. While regulatory T cells (Tregs) are essential for immune homeostasis, clinical evidence have reported paradoxical dynamics (deficiency vs. expansion) of peripheral Tregs in MDD patients. The plasticity of Tregs and microenvironmental reprogramming mechanisms remain elusive, highlighting the need for pathology-driven biomarkers and targeted interventions. In this study, we integrated mass cytometry (CyTOF; n = 37), single-cell RNA/T cell receptor sequencing (n = 10), and flow cytometry (n = 123) to systematically profile Tregs in MDD. Functional assays were conducted to evaluate suppressive capacity, interleukin-6/interferon-γ (IL-6/IFN-γ)-driven plasticity, and diagnostic utility via receiver operating characteristic (ROC) analysis. Results showed that MDD patients exhibit significant peripheral immune dysregulation, notably expanded peripheral Tregs (1.2-fold increase, p = 0.001). Single-cell analysis revealed that these were predominantly T-bet+ Th1-like subpopulations (1.5-fold increase, p = 0.01) displaying mitochondrial dysfunction, elevated IFN-γ response (NES = 1.51), and impaired suppression (16.7 vs. 62.8% inhibition, p < 0.001). IL-6 signaling drove this aberrant differentiation, and IL-6 blockade reversed the inflammatory phenotype (1.8-fold reduction, p < 0.001). Clinically, T-bet+ Th1-like Tregs effectively discriminated drug-naïve MDD patients (area under the curve [AUC] = 0.776, 95% confience interval (CI): 0.668–0.884) and correlated with symptom severity (HAMD score: r = 0.49, p < 0.001). These findings demonstrate that MDD-associated IL-6-driven Th1-like Treg polarization underlies MDD immunopathology, linking metabolic dysregulation with inflammatory conversion, and positions this subset as dual diagnostic biomarkers and therapeutic targets for modulating the IL-6/IFN-γ axis in depression.

Background Acute pancreatitis (AP) is a severe inflammatory disorder in which mitochondrial dysfunction and ferroptosis critically drive acinar cell injury. Our previous work suggested a protective role for exogenous milk fat globule-epidermal growth factor 8 (MFG-E8) in AP. This study aimed to elucidate the molecular mechanism by which endogenous MFG-E8 mitigates mitochondrial damage and ferroptosis during AP.Methods Two mouse models of AP were used for in vivo studies, while cerulein + lipopolysaccharide-induced mitophagy and ferroptosis in AR42J cells (cells of the rat exocrine pancreas) for in vitro studies. Mfge8 gene-defective mice and lentivirus were utilised to downregulate MFG-E8 expression in mice and overexpress MFG-E8 in cells, respectively. Dual gene modification was employed to overexpress MFG-E8 and simultaneously knockdown adenosine triphosphate (ATP)-binding cassette subfamily E member 1 (ABCE1) in vitro. One mitophagy agonist and two ferroptosis inhibitors were used in both in vitro and in vivo experiments.Results Endogenous MFG-E8 expression was downregulated in experimental AP. Genetic deletion of Mfge8 aggravated mitochondrial ultrastructural damage, impaired mitophagy flux and intensified ferroptosis, as evidenced by increased lipid peroxidation, Fe2+ accumulation and depletion of glutathione peroxidase. Lentiviral overexpression of MFG-E8 in AR42J acinar cells restored mitophagy activity, preserved mitochondrial membrane potential and reduced oxidative stress. Mechanistically, co-immunoprecipitation confirmed that MFG-E8 directly interacts with ABCE1, a key mitophagy regulator. ABCE1 knockdown abolished the protective effects of MFG-E8 on mitochondrial function and ferroptosis suppression, indicating that the MFG-E8/ABCE1 axis is essential for maintaining mitophagy homeostasis. Pharmacological restoration of mitophagy or inhibition of ferroptosis rescued acinar cell injury caused by MFG-E8/ABCE1 dysregulation. In vivo, ferroptosis inhibition significantly improved pancreatic pathology and survival in Mfge8-deficient AP mice.Conclusion Endogenous MFG-E8 protects against AP by binding ABCE1 to sustain mitophagy flux and inhibit ferroptosis. Targeting this axis offers a promising therapeutic strategy for mitigating pancreatic injury.Key points Endogenous MFG-E8 is downregulated in acute pancreatitis (AP), disrupting MFG-E8/ABCE1 complex formation. MFG-E8/ABCE1 axis sustains Parkin-PINK1-mediated mitophagy to clear damaged mitochondria in pancreatic acinar cells. This axis suppresses ferroptosis by reducing Fe2+ accumulation and lipid peroxidation, alleviating AP-related pancreatic injury.

Pancreatic fibrosis is an important pathogenesis of chronic pancreatitis (CP), and the activation of pancreatic stellate cells (PSCs) caused by chronic inflammation plays a key role in this process. Cold-inducible RNA-binding protein (CIRP) is a stress response protein involved in acute inflammation and tissue fibrosis. However, its role in pancreatic fibrosis has not been elucidated. Serum CIRP levels were measured in 17 CP patients and 34 healthy controls. Two mouse models of CP (intraperitoneal administration of L-arginine or cerulein) were employed for in vivo studies. CIRP gene knockout (Cirp-KO) was utilized to downregulate CIRP in mice. C23, a specific inhibitor of CIRP, was used to antagonize CIRP activity in experimental CP. NLRP3 inhibitors or disulfiram were used to block pancreatic cell pyroptosis in CP mice. Serum CIRP levels were elevated in both CP patients and in a mouse model of CP. This increase in CIRP was positively correlated with the severity of pancreatic fibrosis and pyroptosis in experimental CP. Genetic deletion of CIRP or intraperitoneal administration of C23 mitigated pancreatic fibrosis in CP mice. Mechanistically, the pro-fibrotic effects of CIRP appear to be mediated through the TLR4 receptor and the induction of pyroptosis. Accordingly, specific inhibition of TLR4 or blockade of pyroptosis effectively reduced pancreatic inflammation and fibrosis in CP mice, without altering serum CIRP levels. Collectively, our data indicate that CIRP plays a significant role in experimental CP. Inhibition of CIRP alleviates pyroptosis and ameliorates the inflammatory microenvironment in pancreatic tissue, thereby retarding the progression of pancreatic fibrosis. This study primarily provides preclinical evidence elucidating a novel mechanism, and the translational relevance to human disease requires further validation.

[This corrects the article DOI: 10.7150/jca.44492.].

BackgroundEmerging evidence supports the role of immune-mediated neuroinflammatory processes and disrupted sleep patterns in elevating susceptibility to major depressive disorder (MDD). Sleep disturbances, a hallmark clinical feature of MDD, have further been linked to changes in lymphocyte profiles. Nevertheless, the potential relationship between sleep disturbance and lymphocyte subpopulations characteristic in patients with MDD remains underexplored.MethodsIn this study, flow cytometry was used to measure the proportion of peripheral blood CD4+ T-helper cells in 63 patients with MDD and 60 age- and sex-matched healthy controls (HCs). The relationship between self-reported sleep disturbances and the proportion of these cells was evaluated using Pearson’s correlation coefficient.ResultsBaseline scores on the Hamilton Depression Rating Scale (HAMD) and Self-Rating Depression Scale (SDS) in patients with MDD were significantly higher than those in HCs. Regardless of antidepressant medication use, patients with MDD exhibited elevated proportions of CD4+ regulatory T cells (Tregs), IFN-γ+-Tregs, IL-4+-Tregs and Th1 (IFN-γ+-CD4+ T) cells compared to HCs. Furthermore, the Pittsburgh Sleep Quality Index (PSQI) scores in patients with MDD showed a positive correlation with CD4+ T cell frequency. Notably, MDD patients with self-reported sleep disturbance had a higher CD4+ T cell percentage than those without such disturbance.ConclusionsOur findings demonstrate that patients with MDD comorbid with sleep disturbances exhibit elevated proportions of CD4+ T cells compared to those without such disturbance. These results suggest that targeted interventions addressing sleep disruption may contribute to restoring CD4+ T cell homeostasis, potentially offering a novel therapeutic strategy for MDD management.

Background: Mitochondrial dysfunction caused by Ca2+ overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca2+, and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. Methods: We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for in vivo studies. For in vitro studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. Trpm4 gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both in vitro and in vivo. Results: Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. Conclusions: TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.

Acute pancreatitis can lead to systemic inflammation and multiple organ damage. Increased endothelial permeability is a hallmark of systemic inflammation. Several studies have demonstrated that cold-inducible RNA-binding protein (CIRP) functions as a proinflammatory factor in various diseases. However, its role in endothelial barrier dysfunction during acute pancreatitis remains unknown. To study this, acute pancreatitis was induced by two hourly intraperitoneal injections of 4.0 g/kg l -arginine in wild-type (WT) or CIRP knockout mice. Our results showed that CIRP levels in the pancreas, small intestine, lung, and liver were upregulated at 72 h after the induction of acute pancreatitis in WT mice. CIRP deficiency significantly attenuated tissue injury, edema, and extravasation of Evans blue in the pancreas, small intestine, lung, and liver at 72 h after l -arginine injection. Administration of C23, a specific antagonist of CIRP, at 2 h after the last injection of l -arginine also produced similar protective effects as CIRP knockout in mice. In vitro studies showed that recombinant CIRP caused a significant reduction in transcellular electric resistance in HUVEC monolayers. Immunocytochemical analysis of endothelial cells exposed to CIRP revealed an increased formation of actin stress fibers. VE-cadherin and β-catenin staining showed intercellular gaps were formed in CIRP-stimulated cells. Western blot analysis showed that CIRP induced SRC phosphorylation at TYR416. Exposure to the SRC inhibitor PP2 reduced CIRP-induced endothelial barrier dysfunction in HUVEC monolayers. In conclusion, blocking CIRP mitigates acute pancreatitis-induced multiple organ damage by alleviating endothelial hyperpermeability. Targeting CIRP may be a potential therapeutic option for acute pancreatitis.

The current study aims to investigate the correlation between mean arterial pressure (MAP) and the risk of 28-day mortality in patients with acute myocardial infarction. This is a retrospective cohort study utilizing data from the eICU database, focusing on patients with acute myocardial infarction. We employed a multivariable logistic regression model to estimate the relationship between MAP and the 28-day mortality rate. Among 8161 patients with a median age of 67 years, 602 (7.38%) died within 28 days of ICU admission. Smooth curve fitting and generalized additive model analysis identified a threshold effect at MAP of 84 mmHg. We found that when MAP is less than 84 mmHg, a 10 mmHg increase in MAP reduces the mortality rate by approximately 40.13%. Specifically, for every 1 mmHg increase in MAP within this range, the mortality rate decreases significantly by 5% (OR = 0.95, 95% CI (0.93, 0.96), p < 0.0001). Conversely, above the threshold (MAP ≥ 84 mmHg), for every 10 mmHg increase, the mortality rate increases by 34.39% (OR = 1.3439, calculated based on the fact that a 1 mmHg MAP increase causes a 3% mortality rise (OR = 1.03, 95% CI (1.02, 1.03), p < 0.0001), showing a U-shaped association between MAP and 28-day mortality. We found that the baseline MAP at ICU admission, when in the range of 57–110 mmHg, was associated with the lowest 28-day all-cause mortality risk. The relationship between MAP and the risk of 28-day mortality forms a U-shaped curve, indicating that both higher and lower MAP levels are associated with an increased risk of 28-day mortality in ICU-admitted patients.

BACKGROUND:Liver injury is common in severe acute pancreatitis (SAP). Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes, which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis. Our previous study found that milk fat globule epidermal growth factor 8 (MFG-E8) alleviates acinar cell damage during SAP via binding to αvβ3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy. AIM:To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux. METHODS:SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50 μg/kg cerulein plus lipopolysaccharide. mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAP-induced liver injury. Cilengitide, a specific αvβ3/5 integrin inhibitor, was used to investigate the possible mechanism of MFG-E8. RESULTS:The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice, enhanced autophagy flux in hepatocyte, and worsened the degree of ferroptosis. Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner. Mechanistically, MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells. Cilengitide abolished MFG-E8's beneficial effects in SAP-induced liver injury. CONCLUSION:MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrin αVβ3/5.

Adiponectin is a pleiotropic cytokine predominantly derived from adipose tissue. In addition to its role in regulating energy metabolism, adiponectin may also be related to estrogen-dependent diseases, and many studies have confirmed its involvement in mediating diverse biological processes, including apoptosis, autophagy, inflammation, angiogenesis, and fibrosis, all of which are related to the pathogenesis of endometriosis. Although many researchers have reported low levels of adiponectin in patients with endometriosis and suggested that it may serve as a protective factor against the development of the disease. Therefore, the purpose of this review was to provide an up-to-date summary of the roles of adiponectin and its downstream cytokines and signaling pathways in the aforementioned biological processes. Further systematic studies on the molecular and cellular mechanisms of action of adiponectin may provide novel insights into the pathophysiology of endometriosis as well as potential therapeutic targets.

Evidence suggests that complex interactions among the gut microbiome, metabolic abnormalities, and brain have important etiological and therapeutic implications in major depressive disorder (MDD). However, the influence of microbiome-gut-brain cross-talk on cognitive impairment in MDD remains poorly characterized. We performed serum metabolomic profiling on 104 patients with MDD and 77 healthy controls (HCs), and also performed fecal metagenomic sequencing on a subset of these individuals, including 79 MDD patients and 60 HCs. The findings were validated in a separate cohort that included 40 patients with MDD and 40 HCs using serum-targeted metabolomics. Abnormal bile acid metabolism was observed in patients with MDD, which is related to cognitive dysfunction. The following gut microbiota corresponded to changes in bile acid metabolism and enzyme activities involved in the bile acid metabolic pathway, including Lachnospiraceae (Blautia_massiliensis, Anaerostipes_hadrus, Dorea_formicigenerans, and Fusicatenibacter_saccharivorans), Ruminococcaceae (Ruminococcus_bromii, Flavonifractor_plautii, and Ruthenibacterium_lactatiformans), and Escherichia_coli. Furthermore, a combinatorial marker classifier that robustly differentiated patients with MDD from HCs was identified. In conclusion, this study provides insights into the gut-brain interactions in the cognitive phenotype of MDD, indicating a potential therapeutic strategy for MDD-associated cognitive impairment by targeting the gut microbiota and bile acid metabolism.

Acute pancreatitis (AP) continues to pose a major challenge as targeted therapeutic interventions are absent. Mitochondrial dysfunction and inflammasome-dependent pyroptosis are involved in the pathogenic mechanisms of AP. CIRP is a stress-response protein and a damage-associated molecular pattern (DAMP) molecule. In our previous studies, we discovered that excessive CIRP can directly damage pancreatic acinar cells. Nonetheless, the precise involvement of CIRP in AP is still unexplored. The primary aim of this study was to examine the potential involvement of CIRP in the development of pyroptosis and mitochondrial dysfunction in AP. To study this, an L-arginine-induced AP mouse model was used. Our results showed that Caspase-1-mediated pyroptosis and mitochondria-derived reactive oxygen species (ROS) were crucial factors in the occurrence of tissue damage and inflammation in AP. A substantial increase in the CIRP serum levels was observed in AP mice. Blocking CIRP by either CIRP gene knockout or systemic administration of C23, a competing inhibitor of CIRP, reduced ROS accumulation and pyroptosis in AP mice. These effects were associated with attenuated pancreatic injury and inflammation. In addition, CIRP-triggered mitochondrial dysfunction, autophagy impairment, and pyroptosis in pancreatic acinar cells were prevented by TAK242, an inhibitor of CIRP receptor TLR4. In conclusion, CIRP can induce mitochondrial dysfunction and pyroptosis in pancreatic acinar cells, and blocking CIRP may be a valuable approach to treating patients with AP.

Pancreatic cancer is an extremely malignant tumor, and only a few clinical treatment options exist. MFG -E8 and kindlin-2 all play an important role in cancer progression. However, the specific mechanism occurring between MFG -E8, kindlin-2 and the migration and invasion of pancreatic cancer cells remains unelucidated. To unravel the specific mechanism, this study assessed the potential association between MFG -E8 and kindlin-2 as well as the involvement of MFG -E8 in pancreatic cancer using two pancreatic cancer cell lines (MiaPaCa-2 and PANC-1). Pancreatic cancer cells were treated with 0, 250, and 500 ng/ml MFG -E8, and the effects of MFG -E8 on the migration, invasion, and anoikis of pancreatic cancer cells were observed. To investigate the role of kindlin-2 in pancreatic cancer, kindlin-2-shRNAi was transfected to knock down its expression level in the two pancreatic cancer cell lines. Furthermore, cilengitide, a receptor blocker of MFG -E8, was used to explore the relationship between MFG -E8, kindlin-2, and pancreatic cancer progression. Our findings demonstrated that MFG -E8 promotes the migration and invasion of pancreatic cancer cells and induces cell anoikis resistance in a dosedependent manner, which was effectively counteracted by cilengitide, a receptor blocker. Additionally, the knockdown of kindlin-2 expression nullified the effect of MFG -E8 on the migration and invasion of pancreatic cancer cells. Consequently, this study provides insights into the specific mechanism underlying the interplay between MFG -E8 and kindlin-2 in the progression of pancreatic cancer cells.

BACKGROUND:Endoplasmic reticulum (ER) stress plays an important role in the occurrence and development of various liver diseases. However, there are no effective prevention and treatment strategies. We aimed to determine the role of heat shock factor 2 binding protein (HSF2BP) in ER stress.METHODS:HSF2BP expression in mice and cultured hepatocytes was measured during ER stress induced by tunicamycin, and its importance in ER stress was evaluated in hepatocyte-specific HSF2BP transgenic (TG) and knockout (KO) mice. The effects and mechanisms of HSF2BP on ER stress were further probed in hepatic ischemia-reperfusion (I/R) injury.RESULTS:HSF2BP expression was significantly upregulated during tunicamycin-induced ER stress in mice and cultured hepatocytes. Liver injury and ER stress were reduced in HSF2BP overexpressing mice after treating with tunicamycin, but were aggravated in HSF2BP knockout mice compared to the controls. In hepatic I/R injury, HSF2BP expression was significantly upregulated, and HSF2BP overexpressing mice had reduced liver injury and inflammation. These improvements were associated with ER stress inhibition. However, these results were reversed in hepatocyte-specific HSF2BP knockout mice. HSF2BP overexpression increased cytoplasmic CDC73 levels and inhibited the JNK signaling pathway. CDC73 knockdown using siRNA eliminated the protection exerted by HSF2BP overexpression in hypoxia/reoxygenation (H/R)-induced ER stress in hepatocytes.CONCLUSION:HSF2BP is a previously uncharacterized regulatory factor in ER stress-likely acts by regulating CDC73 subcellular localization. The feasibility of HSF2BP-targeted treatment in ER stress-related liver disease deserves future research.

[This corrects the article DOI: 10.3389/fcell.2021.803876.].

Severe acute pancreatitis (AP) is associated with a high mortality rate. Cold -inducible RNA binding protein (CIRP) can be released from cells in inflammatory conditions and extracellular CIRP acts as a damage-associated molecular pattern. This study aims to explore the role of CIRP in the pathogenesis of AP and evaluate the therapeutic potential of targeting extracellular CIRP with X-aptamers. Our results showed that serum CIRP concentrations were significantly increased in AP mice. Recombinant CIRP triggered mitochondrial injury and ER stress in pancreatic acinar cells. CIRP-/- mice suffered less severe pancreatic injury and inflammatory responses. Using a bead-based X-aptamer library, we identified an X-aptamer that specifically binds to CIRP (XA-CIRP). Structurally, XA-CIRP blocked the interaction between CIRP and TLR4. Functionally, it reduced CIRP-induced pancreatic acinar cell injury in vitro and L-arginine-induced pancreatic injury and inflammation in vivo. Thus, targeting extracellular CIRP with X-aptamers may be a promising strat-egy to treat AP.

Hepatic ischemia-reperfusion (IR) injury is a complex systemic process causing a series clinical problem. C/EBP alpha is a key transcription factor for hepatocyte function, but its role and mechanism in regulating hepatic IR injury are largely unknown. Occluding portal vein and hepatic artery was used to establish a mouse model of hepatic IR injury. C/EBP alpha expression was decreased in IR-injured liver compared with the sham, accompanied by increased contents of serum alanine transaminase (ALT), aspartate transaminase (AST), high mobility group box-1, and proportion of hepatic cells. Oxygen and glucose deprivation/recovery (OGD/R) was used to establish a cellular hepatic IR model in WRL-68 hepatocytes in vitro, and C/EBP alpha was overexpressed in the hepatocytes to evaluate its effect on hepatic IR injury. OGD/R promoted oxidative stress, cell apoptosis and endoplasmic reticulum (ER) stress in hepatocytes, which was reversed by C/EBP alpha overexpression. Then, we found that C/EBP alpha promoted histone deacetylase 1 (HDAC1) transcription through binding to HDAC1 promoter. Moreover, HDAC1 deacetylated the activating transcription factor 4 (ATF4), a key positive regulator of ER stress. Trichostatin-A (an HDAC inhibitor) or ATF4 overexpression reversed the improvement of C/EBP alpha on OGD/R-induced ER stress and hepatocyte dysfunction. 4-Phenylbutyric acid (an endoplasmic reticulum stress inhibitor) also reversed the hepatic IR injury induced by ATF4 overexpression. Finally, lentivirus-mediated C/EBP alpha overexpression vector was applied to administrate hepatic IR mice, and the results showed that C/EBP alpha overexpression ameliorated IR-induced hepatic injury, manifesting with reduced ALT/AST, oxidative stress and ER stress. Altogether, our findings suggested that C/EBP alpha ameliorated hepatic IR injury by inhibiting ER stress via HDAC1-mediated deacetylation of ATF4 promoter.

Excessive endoplasmic reticulum (ER) stress contributes significantly to the pathogenesis of exocrine acinar damage in acute pancreatitis. Our previous study found that milk fat globule EGF factor 8 (MFG-E8), a lipophilic glycoprotein, alleviates acinar cell damage during AP via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining cellular homeostasis. However, MFG-E8's role in ER stress in pancreatic exocrine acinar cells has not been evaluated. To study this, thapsigargin, brefeldin A, tunicamycin and cerulein + LPS were used to induce ER stress in rat pancreatic acinar cells in vitro. L-arginine- and cerulein + LPS-induced acute pancreatitis in mice were used to study ER stress in vivo. The results showed that MFG-E8 dose-dependently inhibited ER stress under both in vitro and in vivo conditions. MFG-E8 knockout mice suffered more severe ER stress and greater inflammatory response after L-arginine administration. Mechanistically, MFG-E8 increased phosphorylation of FAK and STAT3 in cerulein + LPS-treated pancreatic acinar cells. The presence of specific inhibitors of αvβ3/5 integrin, FAK or STAT3 abolished MFG-E8's effect on cerulein + LPS-induced ER stress in pancreatic acinar cells. In conclusion, MFG-E8 maintains cellular homeostasis by alleviating ER stress in pancreatic exocrine acinar cells.