Ischemia-reperfusion Injury In Transplantation Research Articles

Acute Response of Hepatocyte MRP2 Internalization as an Indicator of Ischemia-Reperfusion Injury in Liver Transplantation.

The introduction of normothermic machine perfusion (NMP) offers new opportunities to evaluate liver graft viability before liver transplantation (LT). Under ischemic stress, multidrug resistance-associated protein 2 (MRP2) translocates from the hepatocyte membrane to the cytoplasm, resulting in loss of function. We measured the cytoplasmic proportion of MRP2 (MRP2 internalization index, MII) by immunofluorescence colocalization analysis using CD13 as a canalicular membrane marker. The data showed that MII significantly correlated with ischemia time in both in situ ischemia-reperfusion injury and NMP rat models (R2 = 0.331, P < 0.0001; R2 = 0.632, P < 0.0001, respectively). Perfusate levels of liver injury markers at the end of NMP showed a significant positive correlation with MII for aspartate aminotransferase (R² = 0.444, P = 0.0013) and arginase 1 (R² = 0.637, P < 0.0001). Conversely, bile production exhibited a significant inverse correlation with MII (R² = 0.618, P < 0.0001). The maximum transport rate of MRP2 (Vmax,MRP2), derived from kinetic modeling of sodium fluorescein biliary excretion, showed a significant inverse correlation with ischemia time (R2 = 0.326, P = 0.0086) and MII (R2 = 0.554, P = 0.0002). In human LT, MII values from donor liver biopsies preLT correlated significantly with peak postLT serum aminotransferase levels (R2 = 0.398, P = 0.0007). MRP2 is a putative biomarker for the assessment of hepatic ischemia-reperfusion injury. The biliary excretion kinetics of sodium fluorescein reflects MRP2-mediated transport activity, providing a novel diagnostic method for predicting liver graft viability after LT.

Transcriptomics-based identification of biomarkers associated with mast cell activation during ischemia-reperfusion injury in kidney transplantation.

Transcriptomics-based identification of biomarkers associated with mast cell activation during ischemia-reperfusion injury in kidney transplantation.

Assessment of Amniotic Fluid as a Preservation Solution in Pig Livers Undergoing Machine Perfusion.

Assessment of Amniotic Fluid as a Preservation Solution in Pig Livers Undergoing Machine Perfusion.

The novel compound PICCS improves cell viability during cold storage and reduces pulmonary ischemia-reperfusion injury in a rat model

A simple method to achieve better organ preservation is the addition of compounds to the preservation solution, which effectively inhibits cold injury. We aimed to develop novel compounds for better lung graft preservation using TY52156 as a seed compound, which reportedly inhibits cold injury of vascular endothelial cells and exerts organ-protective effects in a rat heart transplant model. Eighteen compounds were newly synthesized and screened using an in vitro screening system for cold storage and rewarming. Among them, three of the synthesized compounds increased cell viability after 4 days of cold storage in both vascular endothelial and airway epithelial cells without cytotoxic effects. They were denoted as preventing inducible cell damage in cold stress (PICCS)-1, -2, and -3. PICCS-3 inhibited apoptotic signaling in airway epithelial cells after 6 h of cold storage. In a rat lung transplant ischemia-reperfusion injury (IRI) model, addition of PICCS-3 to the organ preservation solution attenuated IRI, as evidenced by improved physiological data of the lung graft, reduced lung edema, and extravasation of neutrophils. This study demonstrates the potential of a structure-based synthetic approach and an in vitro screening system using appropriate cell types to develop novel effective additives for organ preservation solutions.

Diuretics in critically ill patients: a narrative review of their mechanisms and applications.

Diuretics in critically ill patients: a narrative review of their mechanisms and applications.

MiR-146a engineered extracellular vesicles derived from mesenchymal stromal cells more potently attenuate ischaemia-reperfusion injury in lung transplantation.

The limited donor lung pool for lung transplantation (LTx) is largely due to concerns over ischaemia-reperfusion injury (IRI), a major cause of primary graft dysfunction (PGD). NLRP3 inflammasome activation is known to play a pivotal role in the onset of IRI. While human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) have shown potential in reducing acute lung injury, their effects on NLRP3 activation in the context of LTx remain unclear. In this study, engineered hucMSC-EVs were delivered via nebulisation to mitigate IRI in rat LTx models. We utilised both a rat orthotopic LTx model and a cell cold preservation reperfusion model to evaluate the therapeutic efficacy of hucMSC-EVs. Bulk-RNA sequencing, single-cell sequencing analysis, immunofluorescence and Western blot techniques were employed to assess NLRP3 inflammasome activation and inflammation. Nebulised hucMSC-EVs were efficiently internalised by alveolar macrophages (AMs), significantly reducing lung injury and improving oxygenation in the LTx models. Mechanistically, the engineered hucMSC-EVs, which enhance the expression of miR-146a, can more effectively suppress the activation of the NLRP3 inflammasome by targeting the IRAK1/TRAF6/NF-κB pathway, resulting in decreased levels of IL-1β, IL-18 and other inflammatory cytokines. These findings highlight the potential of miR-146a-modified EVs in modulating innate immune responses to alleviate IRI. Our results demonstrate that nebulised delivery of engineered hucMSC-EVs effectively mitigates IRI in LTx by inhibiting NLRP3 inflammasome activation. This innovative approach presents a promising strategy for enhancing donor lung preservation and improving post-transplant outcomes in LTx. Nebulized Delivery of miR-146a Engineered hucMSC-EVs Mitigates Ischemia-Reperfusion Injury (IRI) in Lung Transplantation. This study demonstrates the therapeutic potential of nebulized, engineered human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) modified with miR-146a to alleviate IRI in rat lung transplantation models. The treatment significantly improved lung oxygenation and reduced inflammation, highlighting the efficacy of this novel approach in enhancing donor lung preservation. Mechanistic Insights: Inhibition of NLRP3 Inflammasome Activation. Engineered hucMSC-EVs efficiently targeted alveolar macrophages and suppressed NLRP3 inflammasome activation through the IRAK1/TRAF6/NF-κB pathway. This modulation of innate immune responses played a crucial role in reducing IRI-induced lung injury and inflammation, offering a promising strategy to manage primary graft dysfunction in lung transplantation. Superior Efficacy of miR-146a-Modified EVs in Reducing Inflammatory Cytokines. The miR-146a modification enhanced the anti-inflammatory properties of hucMSC-EVs, leading to a more significant reduction in pro-inflammatory cytokines (IL-1β, IL-18, and TNF-α) compared to unmodified EVs. This targeted intervention presents a potential therapeutic avenue for improving lung transplant outcomes and mitigating IRI. Innovative Therapeutic Approach: Non-Invasive Nebulization for Direct Lung Delivery. The use of nebulized EVs for direct delivery to donor lungs represents a non-invasive and efficient method for lung-targeted therapy. This strategy could expand the applicability of MSC-EV-based treatments for improving lung transplantation outcomes, particularly in enhancing donor lung preservation during the procurement process.

Benefits of multi-day ex situ perfusion include dampened ischemia reperfusion injury in liver transplantation

Benefits of multi-day ex situ perfusion include dampened ischemia reperfusion injury in liver transplantation

Recipient toll-like receptor 4 determines the outcome of ischemia-reperfusion injury in steatotic liver transplantation in mice.

Recipient toll-like receptor 4 determines the outcome of ischemia-reperfusion injury in steatotic liver transplantation in mice.

Rutaecarpine alleviates hepatic ischemia‒reperfusion injury in liver transplantation by inhibiting inflammatory response and oxidative stress.

Donation after circulatory death (DCD) livers are limited by mandatory warm ischemia and are more susceptible to ischemia‒reperfusion injury (IRI). Inflammation and oxidative stress play key roles in the development of hepatic IRI, and Rutaecarpine (Rut) has anti-inflammatory and anti-oxidative stress effects. The aim of this study was to investigate whether Rut can alleviate hepatic IRI in liver transplantation (LT) and to explore the underlying mechanisms. Rat DCD LT and oxygen-glucose deprivation/reoxygenation (OGD/R) cell models were established to clarify the effect of Rut on hepatic IRI. The key molecules involved in the hepatoprotective effects of Rut were identified through joint analysis of data from LT patients and drug targets. The target was further validated by in silico, in vivo and in vitro experiments. Rut significantly alleviated liver dysfunction, pathological injury, and apoptosis and improved the survival rate of the rats subjected to LT. In addition, Rut significantly inhibited inflammatory response and oxidative stress. Rut also had similar effects on OGD/R-induced hepatocyte injury. Mechanistically, bioinformatics analysis and in vivo and in vitro experiments revealed that PDE4B may be a key target by which Rut exerts its protective effect, and molecular docking and cellular thermal shift assay confirmed this result. The function of PDE4B was studied via gene intervention technology, and the results showed that PDE4B can aggravate hepatic IRI. Furthermore, PDE4B overexpression abrogated the protective effect of Rut on the liver in LT. Rut alleviates hepatic IRI by targeting PDE4B to inhibit inflammation and oxidative stress. These findings highlight the potential of Rut as a drug candidate for the treatment of patients undergoing LT.

Lachnospiraceae-bacterium alleviates ischemia-reperfusion injury in steatotic donor liver by inhibiting ferroptosis via the Foxo3-Alox15 signaling pathway

ABSTRACT Ischemia-reperfusion injury (IRI) is a major obstacle in liver transplantation, especially with steatotic donor livers. Dysbiosis of the gut microbiota has been implicated in modulating IRI, and Lachnospiraceae plays a pivotal role in regulating host inflammatory and immune responses, but its specific role in liver transplantation IRI remains unclear. This study explores whether Lachnospiraceae can mitigate IRI and its underlying mechanisms. We found Lachnospiraceae-bacterium (Lachn.) abundance was significantly reduced in rats with liver cirrhosis. Lachn.-treated rats exhibited improved intestinal permeability, reduced IRI severity in both normal and steatotic donor livers, and decreased levels of neutrophil and macrophage infiltration, and inflammatory cytokines. Multi-omics analysis revealed elevated pyruvate levels in transplanted livers after Lachn. treatment, alongside reduced Alox15 and Foxo3 expression. Mechanistically, Lachn.-derived pyruvate inhibited Alox15 expression and reduced ferroptosis in normal and steatotic donor livers. Furthermore, reduced nuclear translocation of Foxo3 further suppressed Alox15 expression, alleviating IRI, especially in steatotic donor livers. Clinical samples confirmed reduced donor livers IRI in cirrhotic recipients with high Lachn. abundance after liver transplantation. In conclusion, Lachn. alleviates IRI in steatotic donor liver transplantation by inhibiting ferroptosis via the Foxo3-Alox15 axis, providing a potential therapeutic strategy to modulate gut microbiota to alleviate IRI following liver transplantation.

Exploring Potential Complement Modulation Strategies for Ischemia-Reperfusion Injury in Kidney Transplantation.

The complement system plays a crucial role in regulating the inflammatory responses in kidney transplantation, potentially contributing to early decline in kidney function. Ischemia-reperfusion injury (IRI) is among the factors affecting graft outcomes and a primary contributor to delayed graft function. Complement activation, particularly the alternative pathway, participates in the pathogenesis of IRI, involving all kidney compartments. In particular, tubular epithelial cells often acquire a dysfunctional phenotype that can exacerbate complement activation and kidney damage. Currently, complement-modulating drugs are under investigation for the treatment of kidney diseases. Many of these drugs have shown potential therapeutic benefits, but no effective clinical treatments for renal IRI have been identified yet. In this review, we will explore drugs that target complement factors, complement receptors, and regulatory proteins, aiming to highlight their potential value in improving the management of renal IRI.

Abstract 4140326: Predictors of Developing Ischemia-Reperfusion Injury Immediately after Heart Transplantation

Introduction: Post-heart Transplant (HTx) ischemia-reperfusion injury (IRI) is not uncommon and has been associated with an increased risk of rejection and cardiac allograft vasculopathy. IRI may occur due to long ischemia time, high dose inotropes, and technical surgical reasons. Identifying other recipient and donor characteristics that might set patients at higher risk for developing IRI might help inform decision-making and improve patient outcomes. Therefore, we aim to investigate predictors of developing IRI immediately after HTx. Methods: Between 2010 and 2020, we assessed 893 patients undergoing HTx at our center. Recipient and donor characteristics were collected and compared between patients who were noted to have immediate post-HTx (within 30 days) IRI on their endomyocardial biopsy (n=241) vs. those who did not (n=652). Multivariable logistic regression was used to determine predictors of IRI development and included all univariate significant variables with (P&lt;0.1). Outcomes were represented as odds ratios with corresponding 95% confidence intervals. Results: Among 893 patients undergoing HTx, 241 (27%) had IRI within 30 days post-HTx (time to IRI was 14.4 ± 7.3 days). Compared to patients without IRI, those who developed IRI trended towards being older (57 ± 12 vs. 55 ±13 years, P=0.07), were less likely to receive induction therapy with anti-thymocyte globulin (ATG) (43.6 vs. 52.9%, P=0.01), and less likely to be listed with an urgent status at the time of HTx (62.7% vs. 71.9%, P=0.008). Patients listed with an urgent status were on optimal hemodynamic support. No other significant differences were recorded in other pre-transplant or peri-operative recipient characteristics among patients who developed IRI vs. those who did not. In regard to donor characteristics, those who developed IRI received hearts from older donors (37 ± 13.5 vs. 34.9 ± 12.2, P=0.03) and showed a trend toward a higher likelihood of donor-recipient sex mismatch (29.9% vs. 23.6%, P=0.059), regardless of recipient sex. On multivariable logistic regression, only ATG-induction [OR:0.69, 95%CI [0.51-0.93], P=0.015) therapy and urgent status at transplantation [OR:07, 95%CI [0.51-0.96], P=0.028) were significant predictors of IRI development Conclusion: Optimal prioritization of HTx candidates on the waitlist and use of ATG induction therapy seem to protect against immediate IRI post-HTx.

Abstract 4140381: Does Induction Therapy with Anti-thymocyte Globulin Decrease First-year Intimal Thickening in Patients Experiencing Ischemia-Reperfusion Injury Immediately after Heart Transplantation?

Introduction: Post-heart Transplant (HTx) ischemia-reperfusion injury (IRI) is associated with an increased risk of rejection and cardiac allograft vasculopathy (CAV). It has been suggested that induction therapy with anti-thymocyte globulin (ATG) may protect against immediate (in the first 30 days) IRI post-HTx. Additionally, ATG has been associated with reduced first-year coronary plaque progression as assessed by intravascular ultrasound (IVUS) among HTx recipients. Whether ATG can decrease first-year intimal thickening in patients experiencing IRI has not been investigated. Therefore, we aim to examine the clinical outcomes of patients who received ATG induction therapy and experienced immediate IRI post-HTx. Methods: Between 2010 and 2020, we assessed 241 patients undergoing HTx and were noted to have immediate post-HTx IRI on their endomyocardial biopsy. Patients were divided into those who received ATG (n=105) induction therapy vs. non-receivers (n=136). In our program, ATG is given to sensitized patients or those with baseline serum creatinine &gt;2.0 mg/dL to delay the initiation of tacrolimus, which may introduce bias to this study. Endpoints included 1-year freedom from any treated rejection (ATR), acute cellular rejection (ACR, grade 2R or 3R), and antibody-mediated rejection (AMR, pAMR grade ≥1, 3-year survival, and 3-year freedom from non-fatal major adverse cardiac events (NF-MACE, including myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, and stroke). IVUS was performed at 4-8 weeks (baseline) and at 1 year post-HTx. Studied IVUS parameters included first-year average change in maximum initial thickness (MIT) and change in MIT ≥0.5mm. Results: Among patients with immediate post-HTx IRI, patients who received ATG induction therapy (57% were sensitized pre-HTx) remained at high immunological risk at 1 year with significantly lower freedom from ATR and AMR but had similar 3-year survival as compared to those who did not receive ATG (Table 1). No between-group differences were observed in the average 1-year change in MIT or the percentage of patients with ≥0.5mm change in MIT. Conclusion: Induction therapy with ATG did not appear to decrease first-year intimal thickening in patients experiencing IRI immediately post-HTx. Future studies are warranted to mitigate immunological complications and reduce coronary plaque progression in high-risk HTx patients.

Defining the molecular response to ischemia-reperfusion injury and remote ischemic preconditioning in human kidney transplantation

Background Ischemia-reperfusion injury (IRI) inevitably occurs during kidney transplantation and extended ischemia is associated with delayed graft function and poor outcomes. Remote ischemic preconditioning (RIPC) is a simple, noninvasive procedure aimed at reducing IRI and improving graft function. Experimental studies have implicated the kynurenine pathway as a protective mechanism behind RIPC. Methods First, paired biopsies from 11 living kidney donors were analyzed to characterize the acute transcriptomic response to IRI. Second, 16 living kidney donors were subjected to either RIPC (n = 9) or no pretreatment (n = 7) to evaluate the impact of RIPC on the transcriptomic response to IRI. Finally, the effect of RIPC on plasma metabolites was analyzed in 49 healthy subjects. Results There was a robust immediate response to IRI in the renal transcriptomes of living-donor kidney transplantation, including activation of the mitogen-activated protein kinase (MAPK) and epidermal growth factor receptor (EGFR) pathways. Preconditioning with RIPC did not significantly alter the transcriptomic response to IRI or the concentration of plasma metabolites. Conclusions The present data validate living-donor kidney transplantation as a suitable model for mechanistic studies of IRI in human kidneys. The failure of RIPC to alter transcriptomic responses or metabolites in the kynurenine pathway raises the question of the robustness of the standard procedure used to induce RIPC, and might explain the mixed results in clinical trials evaluating RIPC as a method to attenuate IRI.

First-in-Human Phase 2a (ATMIRe) Trial of Ex Vivo Allograft Treatment with iCM012 to Mitigate Ischemia-Reperfusion Injury in Kidney Transplantation

First-in-Human Phase 2a (ATMIRe) Trial of Ex Vivo Allograft Treatment with iCM012 to Mitigate Ischemia-Reperfusion Injury in Kidney Transplantation

Effect of Sodium Thiosulfate Pre-Treatment on Renal Ischemia-Reperfusion Injury in Kidney Transplantation.

We recently reported in a rat model of kidney transplantation that the addition of sodium thiosulfate (STS) to organ preservation solution improved renal graft quality and prolonged recipient survival. The present study investigates whether STS pre-treatment would produce a similar effect. In vitro, rat kidney epithelial cells were treated with 150 μM STS before and/or during exposure to hypoxia followed by reoxygenation. In vivo, donor rats were treated with PBS or 2.4 mg/kg STS 30 min before donor kidneys were procured and stored in UW or UW+150 μM STS solution at 4 °C for 24 h. Renal grafts were then transplanted into bilaterally nephrectomised recipient rats which were then sacrificed on post-operative day 3. STS pre-treatment significantly reduced cell death compared to untreated and other treated cells in vitro (p < 0.05), which corresponded with our in vivo result (p < 0.05). However, no significant differences were observed in other parameters of tissue injury. Our results suggest that STS pre-treatment may improve renal graft function after transplantation.

Pyruvate Carboxylase Attenuates Myocardial Ischemia-Reperfusion Injury in Heart Transplantation via Wnt/β-Catenin-Mediated Glutamine Metabolism.

The ischemia-reperfusion process of a donor heart during heart transplantation leads to severe mitochondrial dysfunction, which may be the main cause of donor heart dysfunction after heart transplantation. Pyruvate carboxylase (PC), an enzyme found in mitochondria, is said to play a role in the control of oxidative stress and the function of mitochondria. This research examined the function of PC and discovered the signaling pathways controlled by PC in myocardial IRI. We induced IRI using a murine heterotopic heart transplantation model in vivo and a hypoxia-reoxygenation cell model in vitro and evaluated inflammatory responses, oxidative stress levels, mitochondrial function, and cardiomyocyte apoptosis. In both in vivo and in vitro settings, we observed a significant decrease in PC expression during myocardial IRI. PC knockdown aggravated IRI by increasing MDA content, LDH activity, TUNEL-positive cells, serum cTnI level, Bax protein expression, and the level of inflammatory cytokines and decreasing SOD activity, GPX activity, and Bcl-2 protein expression. PC overexpression yielded the opposite findings. Additional research indicated that reducing PC levels could block the Wnt/β-catenin pathway and glutamine metabolism by hindering the movement of β-catenin to the nucleus and reducing the activity of complex I and complex II, as well as ATP levels, while elevating the ratios of NADP+/NADPH and GSSG/GSH. Overall, the findings indicated that PC therapy can shield the heart from IRI during heart transplantation by regulating glutamine metabolism through the Wnt/β-catenin pathway.

Systematic review and meta-analysis of the effect of N-acetylcysteine on outcomes after liver resection.

N-Acetylcysteine (NAC) is a recognized antioxidative agent that facilitates the conjugation of toxic metabolites. In recent years, NAC has been routinely used to limit ischaemia-reperfusion injury in liver transplantation. There remains, however, contradictory evidence on its effectiveness in liver resection. This meta-analysis examines the effectiveness of NAC in improving outcomes following hepatectomy. A comprehensive search of the MEDLINE, EMBASE, and Cochrane databases was performed to identify relevant randomized controlled trials (RCTs) published since database inception until November 2023. The outcomes of Day 1 biochemical markers (lactate, ALT, bilirubin, and INR), length of stay, transfusion rates, and morbidity were extracted. Quantitative pooling of data was based on a random-effects model. The study protocol was registered on PROSPERO (Registration no: CRD42023442429). Five RCTs reporting on 388 patients undergoing hepatectomy were included in the analysis. There were no significant differences in patient demographics between groups. Post-operative lactate was lower in patients receiving NAC (WMD -0.61, 95% CI -1.19 to -0.04, I2 = 67%). There were, however, no differences in the post-operative INR (WMD -0.04, 95% CI -0.19 to 0.12, I2 = 96%) and ALT (WMD -94.94, 95% CI -228.46 to 40.38; I2 = 67%). More importantly, there were no statistically significant differences in length of stay, transfusion rates, and morbidity between the two groups. The administration of NAC in liver resection did not alter important biochemical parameters suggesting any real effectiveness in reducing hepatic dysfunction. There were no improvements in the clinical outcomes of length of stay, transfusion rates, and overall morbidity.

Energy Metabolism and Metformin: Effects on Ischemia-Reperfusion Injury in Kidney Transplantation.

Metformin (MTF) is the only biguanide included in the World Health Organization's list of essential medicines; representing a widespread drug in the management of diabetes mellitus. With its accessibility and affordability being one of its biggest assets, it has become the target of interest for many trying to find alternative treatments for varied pathologies. Over time, an increasing body of evidence has shown additional roles of MTF, with unexpected interactions of benefit in other diseases. Metformin (MTF) holds significant promise in mitigating ischemia-reperfusion injury (IRI), particularly in the realm of organ transplantation. As acceptance criteria for organ transplants expand, IRI during the preservation phase remain a major concern within the transplant community, prompting a keen interest in MTF's effects. Emerging evidence suggests that administering MTF during reperfusion may activate the reperfusion injury salvage kinase (RISK) pathway. This pathway is pivotal in alleviating IRI in transplant recipients, potentially leading to improved outcomes such as reduced rates of organ rejection. This review aims to contextualize MTF historically, explore its current uses, pharmacokinetics, and pharmacodynamics, and link these aspects to the pathophysiology of IRI to illuminate its potential future role in transplantation. A comprehensive survey of the current literature highlights MTF's potential to recondition and protect against IRI by attenuating free radical damage, activating AMP-activated protein kinase to preserve cellular energy and promote repair, as well as directly reducing inflammation and enhancing microcirculation.

Human umbilical cord mesenchymal stem cells alleviate fatty liver ischemia-reperfusion injury by activating autophagy through upregulation of IFNγ.

Liver ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of liver transplantation, and extended criteria donors (e.g., steatosis donor livers) are considered to be more sensitive to ischemia-reperfusion injury in liver transplantation. Currently, the application of human umbilical cord mesenchymal stem cells (hMSCs) has great promise in the treatment of various injuries in the liver. This study aimed to investigate the therapeutic role and mechanism of hMSCs in fatty liver IRI. After more than 8 weeks of high-fat chow feeding, we constructed a fatty liver mouse model and established ischemic injury of about 70% of the liver. Six hours after IRI, liver injury was significantly alleviated in hMSCs-treated mice, and the expression levels of liver enzyme, inflammatory factor TNF-α, and apoptotic proteins were significantly lower than those of the control group, which were also significant in pathological sections. Transcriptomics analysis showed that IFNγ was significantly upregulated in the hMSCs group. Mechanistically, IFNγ, which activates the MAPK pathway, is a potent agonist that promotes the occurrence of autophagy in hepatocytes to exert a protective function, which was confirmed by in vitro experiments. In summary, hMSCs treatment could slow down IRI in fatty liver by activating autophagy through upregulation of IFNγ, and this effect was partly direct.