Severe acute pancreatitis (SAP) is a crucial gastrointestinal disease characterized by systemic inflammatory responses and persistent multiple organ failure. The role of bile acids (BAs) in diverse inflammatory diseases is increasingly recognized as crucial, but the underlying role of BA conjugation remains elusive. Our study aim to investigate the potential role of conjugated bile acids in SAP and reveal the molecular mechanisms underlying its regulatory effects. We hypothesized that taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) could protect SAP through inhibiting the activation of NLRP3 inflammasomes via the TGR5 pathway in macrophages. To test our hypothesis, we used BA-CoA: amino acid N-acyltransferase knockout (Baat−/−) mice and established SAP mouse models using caerulein- and sodium taurocholate- induced. We utilized a range of methods, including pathology sections, qRT-PCR, immunofluorescence, Western blotting, and ELISA, to identify the mechanisms of regulation. BA-CoA: Amino acid N-acyltransferase knockout (Baat−/−) mice significantly exacerbated pancreatitis by increasing pancreatic and systemic inflammatory responses and pancreatic damage in SAP mouse models. Moreover, the serum TCDCA levels in Baat−/− mice were lower than those in wild-type (WT) mice with or without SAP, and GCDCA and TCDCA showed stronger anti-inflammatory effects than chenodeoxycholic acid (CDCA) in vitro. TCDCA treatment alleviated SAP in a Takeda G protein-coupled receptor 5 and NOD-like receptor family, pyrin domain containing 3—dependent manner in vivo. Reinforcing our conclusions from the mouse study, clinical SAP patients exhibited decreased serum content of conjugated BAs, especially GCDCA, which was inversely correlated with the severity of systemic inflammatory responses. Conjugated bile acids significantly inhibit NLRP3 inflammasome activation by activating TGR5 pathway, thereby alleviating pancreatic immunopathology. The results provide new insights into the variability of clinical outcomes and paves the way for developing more effective therapeutic interventions for AP.

Severe acute pancreatitis (SAP) is a critical condition characterized by an imbalance between systemic inflammatory response syndrome (SIRS) and compensatory anti‐inflammatory response syndrome (CARS). Disruptions in intestinal microbiota exacerbate this imbalance; however, the mechanisms by which commensal bacteria regulate SAP‐induced SIRS and/or CARS remain unclear. This study reports that the abundance of the gut commensal Akkermansia is significantly reduced in fecal samples from patients with acute pancreatitis (AP) and is inversely associated with the severity of systemic inflammatory responses. Using Foxp3‐DTR and IL‐10‐KO mice, it is found that Akkermansia muciniphila and its derived protein Amuc_1409 can suppress SAP‐induced pancreatic and systemic inflammation by increasing peripheral regulatory T cells (Tregs) and enhancing the IL‐10 expression. Mechanistically, Amuc_1409 interacts with Ube2k to reduce the ubiquitination degradation of Foxp3, and it promotes the differentiation of Tregs and the production of IL‐10, effectively alleviating inflammation induced by SAP. These findings highlight A. muciniphila and its derivative Amuc_1409 as promising probiotic and biomolecule for managing acute pancreatitis and potentially other inflammatory conditions.

The human leukocyte antigen F-associated transcript 10 (FAT10) is a member of the small ubiquitin-like protein family that binds to its target proteins and subjects them to degradation by the ubiquitin–proteasome system (UPS). In the heart, FAT10 plays a cardioprotective role and affects predisposition to cardiac arrhythmias after myocardial ischemia (MI). However, whether and how FAT10 influences cardiac arrhythmias is unknown. We investigated the role of FAT10 in regulating the sodium channel Nav1.5, a major regulator of cardiac arrhythmias. Fat10 was conditionally deleted in cardiac myocytes using Myh6-Cre and Fat10^F/F mice (cFat10^−/−). Compared with their wild-type littermates, cFat10^−/− mice showed prolonged RR, PR, and corrected QT (QTc) intervals, were more likely to develop ventricular arrhythmia, and had increased mortality after MI. Patch-clamp studies showed that the peak Na⁺ current was reduced, and the late Na⁺ current was significantly augmented, resulting in a decreased action potential amplitude and delayed depolarization. Immunoblot and immunofluorescence analyses showed that the expression of the membrane protein Nav1.5 was decreased. Coimmunoprecipitation experiments demonstrated that FAT10 stabilized Nav1.5 expression by antagonizing Nav1.5 ubiquitination and degradation. Specifically, FAT10 bound to the lysine residues in the C-terminal fragments of Nav1.5 and decreased the binding of Nav1.5 to the Nedd4-2 protein, a ubiquitin E3 ligase, preventing degradation of the Nav1.5 protein. Collectively, our findings showed that deletion of the Fat10 in cardiac myocytes led to increased cardiac arrhythmias and increased mortality after MI. Thus, FAT10 protects against ischemia-induced ventricular arrhythmia by binding to Nav1.5 and preventing its Neddylation and degradation by the UPS after MI.

Acute pancreatitis (AP) is currently among the most prevalent digestive diseases. The pathogenesis of AP remains elusive, and there is no specific treatment. Therefore, identifying novel therapeutic targets is imperative for effective management and prevention of AP. In this study, we conducted a comprehensive transcriptomic analysis of peripheral blood from patients with AP and the pancreatic tissue from a mouse model of AP. Our analyses revealed that mouse model of AP exhibited a higher enrichment of mitogen-activated protein kinase signaling, endocytosis, apoptosis and tight junction pathways than the control. Subsequent weighted gene co-expression network analysis identified 15 gene modules, containing between 50 and 1000 genes each, which demonstrated significant correlations within samples from patients with AP. Further screening identified four genes (ACSL4, GALNT3, WSB1, and IL1R1) that were significantly upregulated in severe acute pancreatitis (SAP) in both human and mouse samples. In mouse models of SAP, ACSL4 was significantly upregulated in the pancreas, whereas GALNT3, WSB1, and IL1R1 were not. Lastly, we found that a commercially available ACSL4 inhibitor, PRGL493, markedly reduced IL-6 and TNFα expression, alleviated pancreatic edema and necrosis, and diminished the infiltration of inflammatory cells. In conclusion, this study comprehensively depicts the key genes and signaling pathways implicated in AP and suggests the potential of ACSL4 as a novel therapeutic target for SAP. These findings provide valuable insights for further exploration of therapeutic strategies for SAP.

Sepsis, a life-threatening condition characterized by dysregulated immune responses, poses significant clinical challenges due to high mortality and limited therapeutic strategies. Emerging evidence highlights immune-metabolic dysregulation, particularly in monocytes and macrophages, as a critical driver of sepsis pathogenesis. Here, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from patients with sepsis and healthy controls, revealing significant alterations in immune cell composition. Sepsis patients exhibited increased myeloid cells and decreased T, NK, and B/plasma cells. CD8⁺ T cells displayed enhanced activation, while macrophages showed disrupted amino acid metabolism, with upregulated tryptophan pathways (e.g., CYP1B1, HADHA) and downregulated arginine and proline metabolism. In vitro, lipopolysaccharide (LPS)-stimulated macrophages exhibited elevated CYP1B1 expression, and its inhibition by (E)-2,3′,4,5′-tetramethoxystilbene (TMS) suppressed pro-inflammatory cytokine production (IL1B, TNFA). In a murine sepsis model, TMS administration reduced systemic inflammation, attenuated organ damage, and decreased myeloid cell infiltration. These findings identify CYP1B1 as a novel metabolic checkpoint in sepsis-associated hyperinflammation and demonstrate the therapeutic potential of TMS in rebalancing immune dysregulation. Our study provides insights into precision immunometabolic interventions for sepsis management.