Mast Cell-Derived CXCL4: A Key Mediator of Ferroptosis and Cardiac Damage in Septic Cardiomyopathy.

BackgroundAdvanced stage PBC is characterized by immune response, portal inflammation and liver fibrosis, and can be attributed to enhanced atypical ductular reaction (DR) and biliary senescence. Dominant‐negative transforming growth factor beta receptor II (dnTGFβRII) mice phenotypically mimic some features of late stage PBC at 34 wks of age. MCs infiltrate the liver of humans and murine models of cholestasis, and reside adjacent to bile ducts. Activated MCs release large amounts of tryptase, as well as histamine (HA) that that can act through its specific receptors, H1‐H4 HRs on bile ducts. In models of cholestasis, we have found that blocking MC activation and HR signaling reduces biliary senescence and liver fibrosis. However, the role of MCs and HA signaling during PBC are unknown. The aim of our study was to determine changes in MC and HA signaling during advanced stage PBC, and the therapeutic potential of blocking MCs in our model of advanced stage PBC.MethodsFemale human control and advanced stage PBC samples were analyzed for: (i) MC presence by immunostaining for tryptase and MC‐specific markers by qPCR, (ii) H2HR expression by IHC and qPCR, and (iii) tryptase serum levels by EIA. H2HR expression was evaluated in senescent bile ducts by co‐staining. For in vivo studies we utilized female (i) wild‐type (WT), (ii) dnTGFβRII and (iii) dnTGFβRII treated with cromolyn sodium (24 mg/kg/BW) for 1 wk by intraperitoneally implanted osmotic minipump mice at 34 wks of age. MC presence was determined by staining for chymase and tryptase. MC activation was determined by serum tryptase and HA levels by EIA. H2HR expression was evaluated by immunostaining. Liver damage was evaluated by H&E, and serum levels of ALP and AMA. Atypical DR was visualized by CK‐19 staining and correlated with liver inflammation shown by F4/80 staining. Biliary senescence was determined by qPCR and staining for SA‐β‐Galactosidase, p18 and IL‐1β. Liver fibrosis and hepatic stellate cell activation was assessed by Sirius Red staining and quantification, desmin staining and serum TGF‐β1 levels by EIA.ResultsHuman advanced stage PBC samples showed enhanced hepatic MC number and activation, and activated MCs were found near senescent bile ducts. There was increased hepatic H2 HR expression, which was was upregulated in senescent bile ducts in human advanced stage PBC. dnTGFβRII mice at 34 wks of age had increased MC number/activation, H2HR expression, atypical DR, inflammation, biliary senescence and liver fibrosis; however, all of these parameters were reduced in dnTGFβRII mice treated with cromolyn sodium.ConclusionIncreased MC activation and biliary H2HR expression may drive PBC progression through enhanced biliary senescence that promotes liver fibrosis in a paracrine manner. Inhibition of MC activation via cromolyn sodium treatment may be a therapeutic option for advanced stage PBC patients.Support or Funding InformationNIH NIDDK R01s, VA Merit, Indiana University School of Medicine

Background Sepsis is life-threatening multiple organ failure due to systemic infection, and frequently causes septic cardiomyopathy (SCM). Recent evidence has established that cytokine storm, an aberrant increase in various cytokines leading to severe inflammation and tissue damage, plays a crucial role in SCM. However, it is unknown which cytokines are the most critical initiators and exacerbating factors of SCM. Purpose To investigate how IL-1β and IL-18 driven by NLRP3 inflammasome contribute to the pathophysiology of SCM, and to study whether blockage of these cytokines can ameliorate cardiac dysfunction in a murine model of lipopolysaccharide (LPS)-induced SCM. Methods Wild-type, Nlrp3-/-, Casp1/11-/-, and Il1b-/- mice were injected intraperitoneally with 6 mg/kg of LPS to induce SCM. To suppress IL-18, the adeno-associated virus (AAV) vectors encoding IL-18 binding protein (IL-18BP) were injected intramuscularly 14 days before LPS. Bone marrow transplantation (5 Gy x2) was performed 6 weeks prior to LPS. Results While 40% of wild-type mice died 48 h after LPS injection in our SCM model, none of Nlrp3-/- mice died. Cardiac function, as determined by echocardiography and BNP, was significantly decreased 6 h after LPS injection in WT mice but not in Nlrp3-/- or Casp1/11-/- mice. Serum CK-MB increase was also ameliorated in Nlrp3-/- or Casp1/11-/- mice. Serum levels of various pro-inflammatory cytokines including TNFα, IL-1β, IL-6, IL-18, and IFNγ were suppressed in Nlrp3-/- mice. These findings collectively indicated a critical role of NLRP3 inflammasome in LPS-induced SCM. However, unexpectedly, genetic deletion of IL-1β, the canonical effector molecule of NLRP3 inflammasome, in Il1b-/- mice failed to alleviate cardiac dysfunction and damage caused by LPS. In addition, IL-18 suppression by AAV-mediated overexpression of IL-18BP, a high-affinity IL-18 decoy receptor, only partially prevented LPS-induced SCM. On the other hand, intriguingly, dual inhibition of IL-1β and IL-18 successfully protected mice from LPS-induced SCM, demonstrating that concomitant blockage of two NLRP3 inflammasome products, IL-1β and IL-18, was necessary and sufficient to prevent SCM. Finally, while bone marrow transplantation experiments showed that cardiac dysfunction after LPS injection was suppressed in recipient Nlrp3-/- mice transplanted with wild-type bone marrow cells, cardiomyocyte-specific deletion of NLRP3 in αMHC-Cre;Nlrp3-/- mice did not prevent LPS-induced SCM. These data suggest that NLRP3 inflammasome in resident cells other than bone marrow-derived cells and cardiomyocytes is important in the pathophysiology of SCM. Conclusion The present study indicates that concomitant blockage of IL-1β and IL-18 driven by NLRP3 inflammasome is necessary and sufficient to prevent SCM. Our data provide fundamental evidence that combination therapy targeting both IL-1β and IL-18 could serve as a new approach to the treatment of SCM.

Disclosure: A. Fathi: None. A. Fernandez-Pombo: None. C. Zhu: None. S. Bahriz: None. V.R. Salemme: None. B. Xu: None. J. Lado-Abeal: None. Y.K. Xiang: None.Objective: Septic cardiomyopathy is an early complication of septic shock that increases the risk of death. β-adrenergic receptor (βAR) desensitization leading to decreased ventricular contractility is a key player in septic cardiomyopathy. Tumor necrosis factor-alpha (TNF-α) is a major inflammatory cytokine in sepsis, inhibiting βAR signaling and impairing cardiac function. Non-thyroidal illness syndrome (NTIS), a condition for myocardial hypothyroidism, is a universal complication of septic shock. Thyroid hormones (TH) increase myocardial contractility. We hypothesize that thyroid hormone (T3) replacement can prevent TNF-α-induced βAR desensitization through a thyroid hormone receptor (Thrs) mediated nongenomic mechanism. Methods: Isolated adult ventricular myocytes (AVMs) from mice and rabbits, along with H9c2 myoblast cells, were transfected with FRET-based biosensors to monitor intracellular compartmental cAMP levels (H187) and PKA activity (AKAR3). Protein expression and phosphorylation status were evaluated using Western blot, focusing on phospholamban (PLB). CV1 cells transfected with plasmids encoding Thrα and Thrβ were used to investigate their role in the TH-preventing role on βAR desensitization. Results: TNFα caused a dose-dependent inhibition of isoproterenol (ISO)-induced PKA activity and cAMP increase in AVMs and H9c2 cells. TNFα inhibition was prevented by adding T3 (100 nM) to the cell culture medium 60 min before ISO stimulation. T3 also prevented TNFα-mediated inhibition of ISO-induced PKA phosphorylation of PLB in AVMs. Moreover, T3 prevented the inhibitory effects of TNFα on the ISO-induced increases in calcium transient amplitude and sarcomere shortening in AVMs. Treating the cells with I-850, a compound that inhibits the binding of T3 to Thrs, abolished the T3 preventive effect. Through selective transfection studies in Thr-deficient CV1 cells, Thrα was identified as the receptor mediating T3 effects. Mechanistic investigations revealed that inhibition of PI3K (with Wortmannin) or GRK2 (with Paroxetine) prevents TNFα inhibitory effects on βAR-cAMP-PKA signaling. In AVMs, selective inhibition of PI3Kα or PI3Kγ similarly blocked TNFα effects on β2AR-cAMP-PKA signaling. Conclusion: Our study showed that TNFα-induced desensitization of the βAR and inhibition of calcium transients and sarcomere shortening, a mechanism at the root of septic cardiomyopathy, was prevented by a rapid effect of T3 acting through TRα. These novel findings in thyroid hormone actions open new avenues for future studies investigating the role of thyroid hormone replacement in animal models or humans with septic cardiomyopathy.Presentation: Saturday, July 12, 2025

ObjectivesAlthough extensive research on septic cardiomyopathy has been conducted, effective therapies are still limited. Ubiquitin‐specific peptidase 20 (USP20), a deubiquitinating enzyme, is critical in regulating protein ubiquitination and various cellular processes. whether USP20 is involved in the pathogenesis of septic cardiomyopathy remains unclear. This study investigated the impact of USP20 on septic cardiomyopathy.MethodsThe cardiomyocyte‐specific USP20 knockout mice (USP20CKO) and NLRP3 knockout mice (NLRP3‐/‐) were used in the present study. A sepsis mouse model was established using lipopolysaccharide (LPS) administration and the cecal ligation and puncture (CLP) procedure. Recombinant adeno‐associated virus serotype 9 (AAV9) was used to achieve overexpression of USP20. Myocardial function, histopathological changes, and pyroptosis levels in heart tissues were evaluated. Liquid chromatography tandem mass spectrometry (LC‐MS/MS) analysis and co‐immunoprecipitation (co‐IP) were performed to identify the molecular mechanism of USP20 in septic cardiomyopathy.ResultsOur results showed that USP20 was downregulated in the myocardium of septic mice. Cardiomyocyte‐specific USP20 deficiency worsened myocardial injury and cardiac dysfunction induced by LPS and CLP. LC‐MS/MS analysis and co‐IP revealed NLRP3 as a substrate protein of USP20. Mechanistically, USP20 removed K63‐linked ubiquitin from K243 via its active site C154, inhibiting NLRP3's interaction with ASC and suppressing its activation and subsequent pyroptosis. Moreover, overexpressing USP20 in cardiomyocytes reduced LPS‐induced myocardial injury. Additionally, the protective effect of USP20 against LPS‐induced damage was nullified in the absence of NLRP3 in mice.ConclusionsThese findings suggest that cardiomyocyte‐derived USP20 is crucial in septic cardiomyopathy progression and may serve as a novel therapeutic target for managing septic cardiomyopathy.Key pointsCardiomyocyte‐derived USP20 is crucial in septic cardiomyopathy progression.NLRP3 is identified as a substrate protein of USP20.USP20 deubiquitinates NLRP3 by removing K63‐linked ubiquitin at K243 residue via its active site C154, disrupting the interaction between NLRP3 and ASC, suppressing NLRP3 activation and subsequent pyroptosis.USP20 may serve as a novel therapeutic target for managing septic cardiomyopathy

Ferroptosis is the well-known mechanism of septic cardiomyopathy (SCM). Bioinformatics analysis was employed to identify ferroptosis-related SCM differentially expressed genes (DEG). DEGs' functional enrichment was explored. Weighted gene co-expression network analysis (WGCNA) was employed to form gene clusters. The identified hub genes, signal transducer and activator of transcription 3 (STAT3) and myelocytomatosis (MYC) were further evaluated by generating receiver operator characteristic (ROC) curves and a nomogram prediction model. Additionally, survival rate, cardiac damage markers, and cardiac function and ferroptosis markers were evaluated in septic mouse model. STAT3 and MYC levels were measured in SCM heart tissue via immunohistochemical (IHC) staining, real-time polymerase chain reaction (qPCR) and western blot analysis. Analysis identified 225 DEGs and revealed 22 intersected genes. Of the 7 hub genes, STAT3 and MYC showed enrichment in septic heart tissue and a strong predicative ability based on AUC values. Cardiac damage, iron metabolism, and lipid peroxidation occurred in the SCM model. By experiments, STAT3 and MYC expression was increased in the SCM model. Impairment was reversed with a ferroptosis inhibitor, Fer-1. As conclusion, STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor indicators. KEY MESSAGES: Septic cardiomyopathy (SCM) often leads to high mortality in septic patients, and the diagnostic criteria still remains unclear. Ferroptosis as the pathogenic mechanism of SCM could help predict its progression and clinical outcomes. STAT3 and MYC are related with ferroptosis and may serve as potential SCM predictor biomarkers.

Intestinal barrier dysfunction is a key etiologic factor of irritable bowel syndrome (IBS). Metformin improves intestinal barrier function, although the underlying mechanism has yet to be fully explained. This study evaluates the protective effect of metformin on colonic barrier integrity and explores the underlying cellular mechanisms. IBS-like rats were induced by maternal separation. Metformin was administered daily by gavage at 08:30, and rat pups were then separated from their mother. Visceral hyperalgesia and depression-like behaviors were evaluated by colorectal distension, sucrose preference tests, and forced swimming tests. Intestinal integrity was analyzed using sugar probes and transmission electron microscopy. Inflammatory factors and the levels of corticotropin-releasing factor were assessed by PCR and ELISA. The number of mast cells was evaluated by toluidine blue staining. Protein expression and localization were determined using Western blot and immunochemistry. Metformin pretreatment (a) reduced visceral hypersensitivity to colorectal distension, immobility time and enhanced sucrose consumption; (b) decreased urine lactulose/mannitol ratio and sucralose output; (c) inhibited the dilation of tight junction and prevented claudin-4 translocation; (d) inhibited mast cell activation and downregulated the expression of IL-6, IL-18, tryptase, PAR-2, and ERK activation; (e) inhibited claudin-4 phosphorylation at serine sites and interactions between clau-4 and ZO-1. Metformin may block mast cell activation to reduce PAR-2 expression and subsequently inhibit ERK activation and clau-4 phosphorylation at serine sites to normalize the interaction of clau-4 and ZO-1 and clau-4 distribution. Metformin may be clinically beneficial for patients with IBS or IBS-like symptoms.

Mast cell infiltration and activation in the gallbladder wall: Implications for the pathogenesis of functional gallbladder disorder in adult patients

Traumatic brain injury (TBI) is one of the major health problems worldwide that causes death or permanent disability through primary and secondary damages in the brain. TBI causes primary brain damage and activates glial cells and immune and inflammatory cells, including mast cells in the brain associated with neuroinflammatory responses that cause secondary brain damage. Though the survival rate and the neurological deficiencies have shown significant improvement in many TBI patients with newer therapeutic options, the underlying pathophysiology of TBI-mediated neuroinflammation, neurodegeneration, and cognitive dysfunctions is understudied. In this study, we analyzed mast cells and neuroinflammation in weight drop-induced TBI. We analyzed mast cell activation by toluidine blue staining, serum chemokine C-C motif ligand 2 (CCL2) level by enzyme-linked immunosorbent assay (ELISA), and proteinase-activated receptor-2 (PAR-2), a mast cell and inflammation-associated protein, vascular endothelial growth factor receptor 2 (VEGFR2), and blood-brain barrier tight junction-associated claudin 5 and Zonula occludens-1 (ZO-1) protein expression in the brains of TBI mice. Mast cell activation and its numbers increased in the brains of 24 h and 72 h TBI when compared with sham control brains without TBI. Mouse brains after TBI show increased CCL2, PAR-2, and VEGFR2 expression and derangement of claudin 5 and ZO-1 expression as compared with sham control brains. TBI can cause mast cell activation, neuroinflammation, and derangement of tight junction proteins associated with increased BBB permeability. We suggest that inhibition of mast cell activation can suppress neuroimmune responses and glial cell activation-associated neuroinflammation and neurodegeneration in TBI.

Heparin attenuates symptoms and mast cell degranulation induced by AMP nasal provocation

Patients with sepsis frequently develop septic cardiomyopathy, which is known to be closely related to excessive inflammatory responses. Indole-3-propionic acid (IPA) is a tryptophan metabolite with anti-inflammatory properties that have been demonstrated in various studies. In this study, we investigated the underlying mechanisms and therapeutic role of IPA in septic cardiomyopathy. To investigate the role of IPA in septic cardiomyopathy, we constructed a lipopolysaccharide (LPS)-induced rat model of septic cardiomyopathy, and treated rats with IPA. Inflammatory factors and the NF-κB/NLRP3 pathway were evaluated in myocardial tissues and cells after IPA treatment using RT-qPCR, ELISA, Western blotting, and immunohistochemistry. To further elucidate the role of the aryl hydrocarbon receptor (AhR), we detected changes in inflammatory mediators and the NF-κB/NLRP3 pathway in in vivo and in vitro models of septic cardiomyopathy, which were treated with the AhR antagonist CH-223191 and/or AhR agonist FICZ. IPA supplementation improved cardiac dysfunction in rats with septic cardiomyopathy. IPA reduced inflammatory cytokine release and inhibited NF-κB/NLRP3 signaling pathway in myocardial tissue and in H9c2 cells. CH-223191 impaired the anti-inflammatory effect of IPA in LPS-treated cells, whereas FICZ exerted the same effect as IPA. IPA also exhibited anti-inflammatory activity by binding to the AhR. Our results indicated that IPA attenuated septic cardiomyopathy in rats via AhR/NF-κB/NLRP3 signaling. Our study revealed that IPA improved left heart dysfunction and myocardial inflammation caused by sepsis via AhR/NF-κB/NLRP3 signaling, suggesting that IPA is a potential therapy for septic cardiomyopathy.

Septic cardiomyopathy is associated with mitochondrial damage and endoplasmic reticulum (ER) dysfunction. However, the upstream mediator of mitochondrial injury and ER stress has not been identified and thus little drug is available to treat septic cardiomyopathy. Here, we explored the role of B-cell receptor-associated protein 31 (BAP31) in septic cardiomyopathy and figure out whether melatonin could attenuate sepsis-mediated myocardial depression via modulating BAP31. Lipopolysaccharide (LPS) was used to establish the septic cardiomyopathy model. Pathway analysis was performed via western blot, quantitative polymerase chain reaction and immunofluorescence. Mitochondrial function and ER stress were detected via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. After exposure to LPS, cardiac function was reduced due to excessive inflammation response and extensive cardiomyocyte death. Mechanistically, melatonin treatment could dose-dependently improve cardiomyocyte viability via preserving mitochondrial function and reducing ER stress. Further, we found that BAP31 transcription was repressed by LPS whereas melatonin could restore BAP31 expression; this effect was dependent on the MAPK-ERK pathway. Inhibition of the ERK pathway and/or knockdown of BAP31 could attenuate the beneficial effects of melatonin on mitochondrial function and ER homeostasis under LPS stress. Altogether, our results indicate that ERK-BAP31 pathway could be used as a critical mediator for mitochondrial function and ER homeostasis in sepsis-related myocardial injury. Melatonin could stabilize BAP31 via the ERK pathway and thus contribute to the preservation of cardiac function in septic cardiomyopathy.

Background: Cellular senescence has emerged as a pivotal focus in cardiovascular research. This study investigates the previously unrecognized role of cellular senescence in septic cardiomyopathy (SCM) and evaluates senomorphic therapy using ruxolitinib (Rux) as a potential treatment option. Methods: We employed lipopolysaccharide (LPS)-induced neonatal rat cardiomyocytes (NRCMs) and two mouse models-LPS-induced and cecal ligation and puncture (CLP)-induced SCM models-to assess Rux's effects. RNA sequencing, western blotting (WB), quantitative polymerase chain reaction (qPCR), immunofluorescence, immunohistochemistry, senescence-associated β-galactosidase (SA-β-gal) assay, and other techniques were utilized to investigate underlying mechanisms. Results: Senescence-associated secretory phenotype (SASP) and cellular senescence markers were markedly elevated in LPS-induced NRCMs and SCM animal models, confirmed by the SA-β-gal assay. Rux treatment attenuated SASP in vitro and in vivo, alongside downregulation of senescence markers. Moreover, Rux-based senomorphic therapy mitigated mitochondrial-mediated apoptosis, improved cardiac function in SCM mice, restored the balance of antioxidant system, and reduced reactive oxygen species (ROS) levels. Rux treatment restored mitochondrial membrane potential, mitigated mitochondrial morphological damage, and upregulated mitochondrial complex-related gene expression, thereby enhancing mitochondrial function. Additionally, Rux treatment ameliorated SCM-induced mitochondrial dynamic dysfunction and endoplasmic reticulum stress. Mechanistically, Rux inhibited JAK2-STAT3 signaling activation both in vitro and in vivo. Notably, low-dose Rux and ABT263 showed comparable efficacy in mitigating SCM. Conclusions: This study highlighted the potential significance of cellular senescence in SCM pathogenesis and suggested Rux-based senomorphic therapy as a promising therapeutic approach for SCM.

In addition to its well-known functional agonism at the level of beta(2) adrenergic receptors on airways smooth muscle cells, salbutamol appears to have additional protective effects, possibly through an inhibition of mast cell activation. The aim of this study is to provide the first evidence in vivo of inhibition of human mast cell activation by salbutamol. Nine atopic subjects received placebo and salbutamol (5 mg/mL) 15 min before an adenosine 5' monophosphate (AMP) nasal provocation in a double-blind crossover study design. The nasal lavage was collected from these subjects prior to or 3, 5, 15 or 30 min after the AMP nasal challenge, and concentrations of histamine and tryptase in the nasal lavage were measured. AMP nasal provocation produced considerable sneezing and induced a transient increase in histamine and tryptase release with peak values achieved at 3 min after the challenge in all the subjects studied. Compared with placebo, salbutamol significantly attenuated the release of histamine and tryptase induced by AMP challenge (P=0.048 and 0.020, respectively). Moreover, the AMP-induced sneezing was also inhibited by pre-treatment with salbutamol (P=0.004). Intranasal salbutamol attenuates nasal symptoms and inhibits histamine and tryptase release caused by AMP nasal provocation thus supporting the hypothesis that salbutamol may play an additional protective role in the airways by inhibiting mast cell activation.

Introduction:Septic cardiomyopathy is a sepsis-mediated cardiovascular complication with severe microcirculatory malperfusion. Emerging evidence has highlighted the protective effects of pulsatile flow in case of microcirculatory disturbance, yet the underlying mechanisms are still elusive. The objective of this study was to investigate the mechanisms of N6-methyladenosine (m6A) modification in the alleviation of septic cardiomyopathy associated with extracorporeal membrane oxygenation (ECMO)-generated pulsatile flow.Methods:Rat model with septic cardiomyopathy was established and was supported under ECMO either with pulsatile or non-pulsatile flow. Peripheral perfusion index (PPI) and cardiac function parameters were measured using ultrasonography. Dot blot assay was applied to examine the m6A level, while qRT-PCR, Western blot, immunofluorescence, and immunohistochemistry were used to measure the expressions of related genes. RNA immunoprecipitation assay was performed to validate the interaction between molecules.Results:The ECMO-generated pulsatile flow significantly elevates microcirculatory PPI, improves myocardial function, protects the endothelium, and prolongs survival in rat models with septic cardiomyopathy. The pulsatile flow mediates the METTL14-mediated m6A modification to zonula occludens-1 (ZO-1) mRNA (messenger RNA), which stabilizes the ZO-1 mRNA depending on the presence of YTHDF2. The pulsatile flow suppresses the PI3K–Akt signaling pathway, of which the downstream molecule Foxo1, a negative transcription factor of METTL14, binds to the METTL14 promoter and inhibits the METTL14-induced m6A modification.Conclusion:The ECMO-generated pulsatile flow increases METTL14-induced m6A modification in ZO-1 and attenuates the progression of septic cardiomyopathy, suggesting that pulsatility might be a new therapeutic strategy in septic cardiomyopathy by alleviating microcirculatory disturbance.

Cardiomyopathy commonly occurs after sepsis and is closely associated with high mortality in clinic. Interferon regulatory factor-2 binding protein 2 (IRF2BP2) has been identified as a negative regulator of inflammation, but its role in septic cardiomyopathy is unknown. The current study aims to illuminate the regulatory function of IRF2BP2 on sepsis-induced cardiomyopathy and to explore the underlying mechanisms. Protein expression of IRF2BP2 in response to sepsis-induced cardiomyopathy was examined in the heart of mice challenged by LPS intraperitoneal injection. AAV9-delivered IRF2BP2 overexpression in the heart was applied to evaluate the regulatory role of IRF2BP2 in sepsis-induced myocardial depression, inflammatory response, and cell death. The molecular mechanisms underlying IRF2BP2-regulated cardiomyopathy were explored using western blot screening assay. Primary cardiomyocytes have been isolated to further confirm the role and mechanism of IRF2BP2 during septic cardiomyopathy. IRF2BP2 expression was dramatically increased in the heart of mice after LPS administration. AAV9-mediated IRF2BP2 overexpression significantly improved sepsis-induced cardiac dysfunction, inhibited inflammatory cell infiltration and cytokine production, and blocked cell death after LPS treatment. Mechanistically, IRF2BP2 activated AMPK signaling in cardiomyocytes, while inhibiting AMPK activation largely reversed IRF2BP2-benefited inflammatory suppression and cell survival. These findings clearly demonstrated that IRF2BP2 is a potent suppressor of sepsis-induced myocardial depression and related heart impairment. Targeting IRF2BP2 represents a promising therapeutic strategy for septic cardiomyopathy.