Search Results (356)

Alcohol-associated hepatitis (AH) is the most severe clinical manifestation of alcohol-associated liver disease. Corticosteroids are the only disease-specific therapy shown to improve short-term survival. Currently, no non-invasive markers are available to predict patient response to corticosteroids or long-term survival in AH. This study investigates whether surface antigens on plasma extracellular vesicles (EVs), key mediators of intercellular communication, can reflect the underlying immune dysregulation in AH and serve as prognostic markers. Patients with AH were prospectively enrolled between 2020 and 2024. Blood samples were collected before corticosteroid initiation during the first 24 h of hospitalization. EVs were characterized using nanoparticle tracking analysis, cryo-electron microscopy, and flow cytometry. Interleukin-6 (IL-6), soluble (s)CD62p, Circulating Vascular Cell Adhesion Molecule-1 (sVCAM), tumor necrosis factor receptor superfamily member 1 (TNRFS1a), and Intercellular Adhesion Molecule 1 (ICAM-1) were quantified by ELISA. Key outcome variables included response to corticosteroids and mortality. A total of 46 patients with AH and 28 healthy donors (HD) were included. EV concentration was significantly higher in AH patients than in HD (9.3 × 10¹¹ [IQR 4–24] versus 2.4 × 10¹¹ [IQR 2–4], p = 0.03). Specific EV antigens were associated with key clinical outcomes: CD20 and CD2 levels differed between patients with or without infections (bacterial, viral, and fungal) developed during hospitalization; CD40 and CD146 were elevated in patients who developed acute kidney injury. EVs enriched in monocyte (CD14) and T-reg (CD25) markers were associated with plasma IL-6 levels, while endothelial markers CD105 and CD146 correlated with sVCAM and sCD62p. EVs enriched in platelet (CD49e) and endothelial (CD31) markers were associated with corticosteroid response, whereas EVs enriched with endothelial (CD105 and CD146) and B lymphocyte (CD19) markers were associated with mortality. Overall, EVs enriched in endothelial and monocyte markers may represent a candidate non-invasive tool for predicting corticosteroid response and mortality in AH, aiding risk stratification and early identification of non-responders for timely transplant evaluation. Full article

Objectives: Kadsura coccinea fruit is a traditional medicinal plant rich in dibenzocyclooctadiene lignans, with established hepatoprotective effects. Binankadsurin A (BKA), a dibenzocyclooctadiene lignan isolated from the K. coccinea fruits. This study aims to evaluate its hepatoprotective efficacy in an acetaminophen (APAP)-induced mouse liver injury model. Methods: The structure of BKA was elucidated by HR-ESI-MS, NMR, single-crystal X-ray diffraction and comparison of their data with those of the literature. Mice were randomly divided into five groups: Control, APAP (400 mg/kg, single intraperitoneal injection), APAP + bicyclol (50 mg/kg), APAP + low-dose BKA (50 mg/kg), and APAP + high-dose BKA (100 mg/kg). Untargeted metabolomics, immunohistochemistry, Western blot analysis, and molecular docking were performed. Results: BKA was determined as a dibenzocyclooctadiene lignan, and the single-crystal structure is reported for the first time. The untargeted metabolomics revealed that metabolites and pathways are closely associated with oxidative stress. In vivo studies showed that pretreatment with BKA can mitigate liver injury. BKA reduced serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and stored hepatic glutathione (GSH) levels. Immunohistochemical analysis results also showed that CYP2E1 expression in the mouse liver could be improved through BKA pretreatment. Furthermore, Western blot analysis presented that BKA could increase the protein expression of Nrf2, HO-1, and NQO-1. Additionally, molecular docking indicated that BKA directly blocks the binding site of Nrf2 with Keap1. Conclusions: BKA reduces APAP-induced acute liver damage by inhibiting oxidative stress by activating the Keap1/Nrf2/HO-1 signaling pathway, providing a theoretical basis for BKA as a potential therapeutic agent for APAP-induced liver injury. Full article

The main objective of this study was to preliminarily analyze the major flavonoid and phenolic acid components of the ethanolic extract of Gerbera delavayi Franch (E-GDF), and to evaluate its anti-inflammatory and antioxidant properties in lipopolysaccharide (LPS)-stimulated murine macrophage RAW264.7 cells and systemic inflammation mouse models. Results indicated that E-GDF was rich in flavonoids (16.35 ± 0.19 mg RT/g d.w. Plant Material) and polyphenolic compounds (36.15 ± 0.20 mg GAE/g d.w. Plant Material). LC-MS analysis of E-GDF revealed that its major flavonoid components included kaempferol glycosides, luteolin, and their glycosylated derivatives, while its phenolic acids were predominantly chlorogenic acid, caffeic acid, ferulic acid, and their corresponding glycosides. E-GDF exhibited good antioxidant activities, including the scavenging of DPPH, ABTS, ^•OH, and O₂^•− radicals. E-GDF treatment significantly inhibited the production of ROS and inflammatory mediators (NO, IL-6, TNF-α) in LPS-stimulated macrophages (RAW 264.7), while concurrently down-regulating the mRNA expression of COX-2, IL-1β, Casp1, and GSDMD-1. In addition, in vivo experiments revealed that E-GDF treatment effectively reduced the serum LPS, AST levels, as well as hepatic TNF-α, IL-6 levels in mice with LPS-induced acute liver injury. Furthermore, E-GDF significantly ameliorated LPS-induced liver pathological damage. These results provide a basis for G. delavayi as a potential antioxidant, anti-inflammatory, and hepatoprotective herbal medicine. Full article

Background: Chemokine CCL5 may drive inflammation and vascular risk in advanced liver disease, but its cardiovascular implications are unclear. Secreted by hepatic, endothelial, macrophage, and lymphocytic cells, CCL5 is involved in cytokine regulation. Its serum levels rise in acute liver injury and hepatocellular carcinoma (HCC), but decline with fibrosis progression in end-stage liver disease (ESLD). CCL5 has also been linked to atherosclerosis. This study aimed to evaluate serum CCL5 levels in ESLD patients listed for liver transplantation (LT) and to assess their potential role as markers of cardiovascular (CV) risk and portal hypertension. Methods: We conducted an observational cohort study. Between 2019 and 2022, patients with ESLD evaluated for LT were enrolled. Data on liver pathology, CV risk, and laboratory parameters were collected. Serum CCL5 concentrations were measured using Sigma Aldrich^® CCL5 ELISA kits (MilliporeSigma, St. Louis, MO, USA). The database was analyzed with IBM^® SPSS^® Statistics version 20 (Chicago, IL, USA). Results: Overall, 46 patients were included, 50% with viral hepatitis and 28.3% with alcohol-related liver disease. HCC was present in 37% of cases. The median CV risk scores (CAD_LT = 7, mCAD_LT = 7, CAR_OLT = 18) placed the population at moderate CV risk. Serum CCL5 levels did not vary significantly between viral vs. non-viral cirrhosis (5511.8 vs. 6272.5 pg/mL, p = 0.15) and were not influenced by the presence of HCC (6098.4 vs. 5771.3 pg/mL, p = 0.55). We did not detect a correlation with MELD score (p = 0.21) or CV risk scores (CAD_LT: p = 0.58; mCAD_LT: p = 0.70; CAR_OLT: p = 0.22). Patients with thrombocytopenia (<100,000/µL, 54.3%) or a history of esophageal variceal ligation had lower CCL5 levels (5170.9 vs. 6750.8 pg/mL, p = 0.002 and 4252.0 vs. 6237.5 pg/mL, p = 0.003, respectively). Similarly, patients with a history of previous variceal bleeding and spontaneous bacterial peritonitis (SBP) had lower levels of CCL5 (4373.8 vs. 6119.9 pg/mL, p = 0.02 and 3404.3 vs. 6606.7 pg/mL, p = 0.01, respectively). We found a negative correlation between CCL5 and QTc interval duration (τ = −0.216, p = 0.037), left ventricle size (LV: τ = −0.235, p = 0.027), and pulmonary artery pressure (RV/RA gradient: τ = −0.225, p = 0.03). CCL5 correlated positively with the inflammatory markers C-reactive protein (CRP) (τ = 0.246, p = 0.018) and fibrinogen (r = 0.216, p = 0.04). Conclusions: In liver transplant candidates, serum CCL5 is not associated with cardiovascular risk scores or coronary atherosclerotic burden, but is inversely associated with clinical markers of portal hypertension severity. These findings suggest that CCL5 may serve as a potential non-invasive surrogate marker of portal hypertension rather than a cardiovascular risk biomarker in ESLD. Full article

Hepatic ischemia–reperfusion injury (IRI) is a critical clinical condition associated with liver transplantation and acute liver injury. This study investigated the role of sulfide quinone oxidoreductase (SQOR) and its downstream product, supersulfides, in hepatic IRI. C57BL/6NJ mice were subjected to 45 min of partial hepatic ischemia, followed by reperfusion lasting 4 h. Control of shRNA mediated knockdown of SQOR expressing adeno-associated viral vectors were administered 3 weeks prior to liver ischemia. In the shRNA-mediated knockdown of SQOR group, the hydro-trisulfide donor sodium trisulfide was administered daily for 1 week prior to the induction of liver ischemia. SQOR played a crucial protective role during hepatic IRI by facilitating electron transport to the mitochondrial respiratory chain and maintaining the oxidized and reduced nicotinamide adenine dinucleotide ratio. Administration of sodium trisulfide, exhibited protective effects against hepatic IRI. Sodium trisulfide restored the oxidized and reduced nicotinamide adenine dinucleotide ratio, reduced oxidative stress, and preserved the expression of key enzymes involved in the sulfide oxidation pathway. SQOR and supersulfides contribute to hepatic protection against IRI, likely through their potent antioxidative and redox-regulating functions, and highlight sodium trisulfide as a potential therapeutic agent. Full article

Background: Methanol poisoning remains a major cause of fatal toxic exposures worldwide, yet the diagnostic value of postmortem methanol and formic acid levels in relation to organ-specific pathology is not fully understood. This study aimed to provide a comprehensive forensic and diagnostic evaluation of fatal methanol intoxications using multiple biochemical and pathological parameters. Methods: A total of 138 autopsy-confirmed methanol poisoning cases were retrospectively analyzed. Quantitative methanol and formic acid levels were measured in blood and vitreous humor. Autopsy reports, demographic characteristics, and histopathological findings in major organs were systematically reviewed. The presence of ethanol and other substances, including stimulants and narcotic drugs, was also recorded. Results: Blood methanol concentrations averaged 142.47 ± 139.20 mg/dL (range: 0–595), and formic acid levels averaged 258.62 ± 197.89 mg/dL (range: 0–618). Vitreous humor concentrations showed comparable distributions. Common pathological findings included cerebral edema, putaminal discoloration or necrosis, myocardial ischemia, hepatic steatosis, pulmonary edema, and acute pancreatitis. Ethanol or other substances were detected in several cases, with stimulants or narcotic drugs present in 10.4% (n = 13). Importantly, the combined interpretation of postmortem biochemical markers and organ pathology allowed clearer differentiation of methanol-related injury patterns compared with prior reports. Conclusions: Methanol intoxication produces variable but characteristic biochemical and pathological profiles. Integrating toxicological markers with organ-specific pathology enhances the diagnostic accuracy of postmortem evaluations and supports more reliable identification of methanol-related deaths. Full article

Diabetic wounds exhibit impaired immune function, delayed neutrophils recruitment, and heightened infection risk which compromises early infection control and delays healing. We have demonstrated that topical CCL3 treatment restores neutrophil influx, reduces bacterial infection by ~99%, and accelerates wound healing in diabetic mice. As per Food and Drug Administration (FDA) Guidelines for Investigational New Drug (IND), we conducted a 14-day acute toxicity study in diabetic mice following a single topical administration of CCL3 at effective low dose (1 µg) and high dose (10 µg) per wound. Mice were monitored for clinical signs, body weight, and food intake throughout the study period. On day 14, serum biochemistry (ALT, AST, BUN, creatinine, metabolic markers) and histopathology of major organs (liver, kidney, heart, lungs, spleen) were assessed. CCL3-treated diabetic mice exhibited no adverse clinical effects. Hematological and biochemical parameters remained within normal limits, and histopathological analyses revealed no additional organ injury in CCL3-treated groups compared to diabetic control mice. Intriguingly, CCL3-treated mice showed improved ALT levels and reduced hepatic pathology, suggesting hepatoprotective effects and reduced serum IgG, indicating reduced systemic inflammation. Overall, our study demonstrates that diabetic mice tolerate topical CCL3 at doses up to 10 times the effective therapeutic concentration without evidence of systemic organ toxicity. These findings provide strong preclinical support for the translational development of CCL3 as a novel therapy for diabetic wound care. Full article

Background/Objectives: Sex-specific differences in the mechanisms of acute liver injury remain poorly understood. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) is crucial for liver development and endoplasmic reticulum (ER) homeostasis. This study aimed to investigate sex-dependent changes in CDK5RAP3 expression in a carbon tetrachloride (CCl₄)-induced acute liver injury model and to explore the mechanisms underlying differential susceptibility between males and females. Methods: Acute liver injury was induced in male and female mice by CCl₄ administration. Liver injury was evaluated by serum biochemical parameters and histopathological analysis. CDK5RAP3 expression, inflammatory cytokines, and ER stress-related apoptotic markers were assessed. Hepatocyte apoptosis was examined by TUNEL staining. In addition, CDK5RAP3 was conditionally deleted in mouse embryonic fibroblasts (MEFs) using 4-hydroxytamoxifen to assess its direct role in regulating inflammatory and apoptotic responses in vitro. Results: CCl₄ exposure caused liver injury in both sexes, with male mice showing more severe biochemical and histological damage. CDK5RAP3 expression was significantly reduced after CCl₄ treatment, particularly in males. Inflammatory mediators and ER stress-associated apoptotic markers were upregulated, accompanied by increased hepatocyte apoptosis. A similar enhancement of inflammatory and apoptotic signaling was observed in CDK5RAP3-deficient MEFs. Conclusions: Downregulation of CDK5RAP3 is associated with ER stress, inflammation, and apoptosis, contributing to increased susceptibility of male mice to acute liver injury. These findings provide insight into sex-specific mechanisms of hepatic injury and highlight CDK5RAP3 as a potential therapeutic target. Full article

Acute liver injury (ALI) is a potentially life-threatening condition lacking effective clinical drugs. Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of both inflammation and metabolism. In ALI, HIF-1α expressions are upregulated, but the role of HIF-1α in hepatocytes and whether it can be targeted remain unclear. Herein, clinical samples and ALI murine models including lipopolysaccharide/D-galactosamine (LPS/D-GalN), acetaminophen (APAP), and thioacetamide (TAA) revealed an increase in HIF-1α expression and ferroptosis. Using HIF-1α gain and loss of function mouse and hepatocyte culture models, we demonstrated that HIF-1α upregulation exacerbated liver ferroptosis and injury. Mechanistically, HIF-1α/transferrin receptor protein 1 (TFR1) axis drives hepatic iron overload, promoting ferroptotic cell death and liver injury. In addition, TFR1 inhibition reversed HIF-1α-induced ALI. Importantly, pharmacological inhibition of HIF-1α and TFR1 significantly reduced ferroptosis and mitigated liver injury both in vivo and in vitro. Together, our findings demonstrate the pathological role of hepatic HIF-1α, which may serve as a promising target of therapeutic intervention. Full article

Background/Objectives: Acetaminophen (paracetamol or APAP) overdose is a major cause of acute liver injury mediated by oxidative stress, inflammation, and hepatocellular necrosis. The present study investigates the in vivo hepatoprotective potential of morin (M), lignin nanoparticles (LN), and morin-encapsulated lignin nanoparticles (LMN) against APAP-induced hepatotoxicity in mice. The specific goal was to determine whether LMN could strengthen hepatic antioxidant and anti-inflammatory defenses prior to toxic insult, which aligns with a prophylactic model rather than a post-injury clinical rescue approach. This study was guided by the primary hypothesis that LMN pretreatment would markedly reduce APAP-induced hepatic injury. Methods: Experimental groups included control, APAP, M, LN, LMN, M+APAP, LN+APAP, and LMN+APAP treatments. Serum hepatic biomarkers, oxidative stress parameters, and inflammatory cytokines were analyzed to assess protective responses. Results: APAP exposure markedly elevated aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels, indicating severe hepatic dysfunction, accompanied by increased lipid peroxidation and pro-inflammatory cytokine production. LMN+APAP treatment significantly restored hepatic enzyme levels to approximately normal values and suppressed malondialdehyde (MDA) formation, while enhancing superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities. LMN also downregulated interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin 1β (IL-1β), while upregulating interleukin 10 (IL-10), suggesting effective attenuation of inflammatory signaling. Correlation analyses demonstrated positive interactions between MDA, cytokines, and hepatic enzymes, whereas antioxidant enzyme levels were inversely correlated with liver injury markers. Histopathological analysis revealed that treatment with LMN enhanced hepatoprotection, demonstrating predominantly mild, reversible lesions and suggesting a synergistic antioxidant and immunomodulatory effect. Conclusions: It could be concluded that LMN provided superior hepatoprotection compared to M or LN. These findings establish LMN as a promising bio-based nanotherapeutic agent for mitigating drug-induced hepatotoxicity through coordinated antioxidant and anti-inflammatory mechanisms. Full article

Background: The GRACE score is widely used to estimate early mortality in acute coronary syndromes (ACS), yet its ability to capture the complex interaction between inflammation, hepatic dysfunction, renal impairment, and myocardial injury remains limited. Integrating biomarkers that reflect these complementary physiological pathways may enhance risk prediction and allow earlier identification of high-risk patients. This study evaluated whether a multi-biomarker model incorporating the C-reactive protein/albumin ratio (CAR), the albumin–bilirubin (ALBI) score, and the blood urea nitrogen/creatinine (BUN/Cr) ratio provides incremental prognostic value beyond the GRACE score and traditional cardiac markers. Methods: This retrospective study included patients hospitalized with ACS. Baseline laboratory results were used to calculate CAR, ALBI, and BUN/Cr ratios. Troponin and hemoglobin values were recorded as standard cardiac and hematologic indicators. The primary outcome was in-hospital mortality. Logistic regression models, receiver operating characteristic (ROC) curve analysis, and comparisons of area under the curve (AUC) were performed to determine whether the multi-biomarker model improved risk stratification beyond the GRACE score alone. Results: Higher CAR, ALBI, and BUN/Cr values were each associated with increased in-hospital mortality. When combined with the GRACE score, the multi-biomarker model significantly improved predictive accuracy. The integrated model demonstrated a higher AUC compared with GRACE alone, indicating incremental prognostic value across inflammatory, hepatic, and renal pathways. Conclusions: A multi-biomarker strategy combining CAR, ALBI, and BUN/Cr ratios enhances early mortality prediction beyond the GRACE score in patients with ACS. Incorporating these readily available laboratory indices may help clinicians identify high-risk patients more precisely at the time of hospital admission. Full article

Water alkalinization is a critical global stressor for freshwater fish, yet the systemic patterns of multi-organ responses and injury remain insufficiently understood. This study integrates histopathology, biochemistry, and multi-organ transcriptomics to provide an integrated, time-resolved assessment of stress responses in European perch (Perca fluviatilis) exposed to acute alkaline stress (20 mmol/L). The analysis indicated that alkaline stress initially causes structural disturbance of gill tissue (lamellar fusion, necrosis) within 96 h, associated with impaired osmoregulatory functions. This primary dysfunction was followed by progressive hepatic impairment, characterized by uncontrolled oxidative stress (elevated levels in Malondialdehyde, MDA) and widespread hepatocyte necrosis. Transcriptomic analysis identified extensive transcriptional shifts associated with these alterations: large-scale differential expression in the liver (3629 Differentially Expressed Genes, DEGs) and kidney (478 DEGs). Notably, the liver exhibited a stress-responsive transcriptional profile involving activation of the HIF-1 signaling pathway and mobilizing protein quality control systems (e.g., ‘Proteasome,’ ‘Lysosome’) consistent with mitigation of proteotoxic stress. This compensatory response appeared insufficient to prevent severe metabolic disruption and cellular injury. This study presents a time-associated sequence of organ-specific stress responses under acute alkalinity, identifying candidate stress-associated genes (slc7a11, egln3, klhl38b) as potential targets for future functional studies and breeding alkali-tolerant strains. Full article

This study evaluated hepatic pathological and phenotypic alterations, along with the inflammatory response, following sequential dengue virus (DENV) infection in Callithrix penicillata, a relevant model for human endemic scenarios. Twenty-six animals were initially infected subcutaneously with DENV-3. Thirteen were euthanized between 1 and 7 days post-infection (dpi) to assess the acute phase, and up to 60 dpi for the convalescent phase. The remaining animals received a secondary DENV-2 infection two months later. Liver samples underwent histopathological and immunohistochemical analysis. Viral antigens were identified in hepatocytes, Kupffer cells, and Councilman bodies. Observed liver changes included apoptosis, lytic necrosis, midzonal inflammation, Kupffer cell hyperplasia and hypertrophy, sinusoidal dilation, and hemosiderin deposition. Both primary and secondary infections increased activated macrophages, NK cells, S-100 protein, and B lymphocytes. Primary infection was associated with elevated CD4⁺ T cells, IFN-γ, TGF-β, IL-10, and Fas expression, whereas secondary infection induced higher IFN-γ, TNF-α, IL-8, Fas, and VCAM levels. These findings mirror hepatic alterations in severe human dengue cases and underscore the role of direct viral effects and immune dysregulation in liver injury. The results support C. penicillata as a suitable non-human primate model for studying DENV pathogenesis. Full article

Background: Ibrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), has revolutionized the treatment of Chronic Lymphocytic Leukemia (CLL), yet hepatotoxicity remains a rare and poorly characterized adverse event. Case Presentation: We report the case of a 54-year-old man with progressive CLL and radiologically confirmed hepatic involvement who developed acute hepatocellular injury during ibrutinib monotherapy. Baseline liver tests showed mild abnormalities attributed to hepatic steatosis and leukemic infiltration. After approximately 10–12 weeks of ibrutinib (420 mg/day), transaminases markedly increased (ALT 660 U/L, AST 326 U/L), while bilirubin and synthetic function remained normal. Viral, autoimmune, and obstructive causes were excluded. Stepwise dose reductions to 140 mg/day provided limited benefit. The addition of prednisone (50 mg/day) led to rapid biochemical improvement. Ibrutinib was successfully re-escalated to 280 mg/day alongside venetoclax initiation, maintaining disease control without recurrence of liver injury. Discussion: The temporal relationship, exclusion of alternative causes, and corticosteroid responsiveness suggest an ibrutinib-induced liver injury, possibly exacerbated by pre-existing hepatic steatosis and leukemic infiltration. Conclusions: This case underscores the multifactorial pathogenesis of BTKi-related hepatotoxicity and highlights the potential role of corticosteroids in management. Prompt recognition, stepwise dose adjustment, and corticosteroid therapy may enable continued treatment and sustained disease control in selected patients. Full article

Background: Orthotopic heart transplantation (OHT) remains the gold standard for end-stage heart failure, yet individualized risk assessment for postoperative mortality remains challenging. We aimed to develop and interpret random forest-based models for predicting 30-day and 1-year mortality and to examine whether the key predictors differ between the 30-day and 1-year models. Methods: We analyzed 581 patients who underwent OHT between 2012 and 2024. The 30-day and 1-year mortality rates were 9.9% and 17.6%, respectively. Eighty-seven preoperative and forty-eight postoperative variables were considered as input features for model development. Random forest models were trained and validated using five-fold cross-validation, and explainability was assessed using SHapley Additive exPlanations (SHAP). Results: Using preoperative features only, the random forest models achieved AUCs of 0.62 (95% CI, 0.48–0.75) for 30-day and 0.67 (95% CI, 0.56–0.78) for 1-year mortality. SHAP analysis revealed that early mortality predictions were primarily driven by features reflecting acute physiological stress—hepatic dysfunction, inflammation, and hemodynamic instability—whereas long-term predictions were increasingly influenced by renal function, metabolic reserve, and frailty. Incorporating postoperative features improved performance (AUC 0.98 [95% CI, 0.97–0.99] and 0.86 [95% CI, 0.80–0.92], respectively), with model predictions dominated by the severity and persistence of organ dysfunction: short-term risk driven by hepatic injury, hemodynamic compromise, and critical illness, and long-term risk by sustained hepatic and renal impairment, metabolic resilience, and duration of circulatory support. Conclusions: Random forest models integrating preoperative and immediate postoperative data could predict short- and mid-term mortality after OHT. SHAP analysis demonstrated temporal shifts in the most important predictors, supporting the role of dynamic, data-driven risk assessment in transplant care. Full article