Liver toxicity is common in patients treated with immune checkpoint inhibitor (ICI) therapy. Most guidelines advocate for the admission of patients with grade 3/4 ICI mediated hepatitis. Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. An ambulatory pathway for ICI mediated hepatitis (CTCAE grade 3/4) was commenced in March 2023. Patients with ICI mediated hepatitis with normal synthetic liver function (bilirubin <30µmol/L, INR <1.5, albumin >30 g/L and grade ≤2 encephalopathy) were considered as potential candidates for acute ambulatory management. Patients received either ambulatory intravenous methylprednisolone 1 mg/kg for 2-3 days or 1 mg/kg oral prednisolone. The primary outcome measure was 30-day readmission due to progressive/refractory hepatitis. Secondary outcome measures were decision to rechallenge with ICI therapy and 30-day all-cause mortality. Eighty-nine patients treated with ICI therapy presented with grade ≥ 3 transaminase rises during the study period. Thirty-eight patients were diagnosed with ICI mediated hepatitis of whom 23 (59%) patients were managed on the ambulatory pathway.Ambulatory pathway patients had a median age of 62 years (37-78) and 10 (43.5%) were male. Median ALT was 323 u/L (range 10-49 u/L) and AST 302 u/L (range 0-33 u/L).No patients required admission due to failure of ambulatory management or worsening liver function. No patients died of any cause within 30 days. Our ambulatory care pathway has been utilised successfully to treat patients with severe ICI-mediated hepatitis. There were no observable adverse outcomes including readmissions and deaths. The adoption of this pathway for appropriate patients could potentially lead to a reduction in hospital admissions, reducing the financial burden of toxicity care, improved patient outcomes and enhancing patient experience.

Preoperative endoscopic retrograde cholangiopancreatography (ERCP) with biliary stent placement is commonly employed in patients with choledocholithiasis as part of a staged perioperative management strategy. In clinical practice, biliary stent migration is often observed at the time of planned postoperative ERCP. Characterizing the occurrence of biliary stent migration, its associated clinical factors, and its implications for postoperative management is therefore relevant to optimizing patient care. We conducted a single-center retrospective cohort study including adult patients who underwent a single preoperative ERCP with biliary plastic stent placement, followed by cholecystectomy and a planned postoperative ERCP for stent removal between 2012 and 2023. The primary outcome was biliary stent migration, defined as absence of the stent at postoperative ERCP, confirmed endoscopically and fluoroscopically. Demographic, clinical, and procedural variables were analyzed to explore factors associated with stent migration. A total of 208 patients were included. Biliary stent migration was observed in 51 patients (24.5%). At postoperative ERCP, choledocholithiasis was identified in 67.8% of cases. In univariate analysis, pancreatic stent placement during the index ERCP was associated with lower odds of biliary stent migration; however, this association did not remain statistically significant after multivariable adjustment. No other demographic or procedural factors were independently associated with migration. Individualized approach may be applied for selective patients referred to the biliary stent removal after cholecystectomy. Abdominal imaging before postoperative ERCP in asymptomatic patients with normal liver function tests may help in the decision-making process and potentially prevent unnecessary invasive procedures and reduce its complications.

Embryonic livers undergo extensive vascular expansion after midgestation to support rapid growth and evolving functions. Immature embryonic vessels receive structural support from extracellular matrix (ECM), which is also essential for normal liver development and function. Meanwhile, pro-inflammatory cytokines that promote hematopoiesis and hepatic organogenesis must be tightly regulated to prevent sterile inflammation. However, endothelial contributions to ECM and cytokine production during liver development remain poorly understood. Here we demonstrate that the chromatin remodelers CHD4 and BRG1 act antagonistically in embryonic endothelial cells to protect developing livers from lethal degeneration. Transcriptomic analysis of endothelial Chd4 mutant livers revealed increased activity of plasmin (an ECM protease) and sterile inflammation before the onset of overt phenotypes. Within these pathways, we found that endothelial CHD4 and BRG1 antagonistically regulate transcription of the plasmin activator uPAR and of the inflammatory adhesion molecule ICAM-1 in developing livers. Our genetic and pharmacological data demonstrate that elevated plasmin activity and sterile inflammation synergistically contribute to hepatic degeneration. These findings highlight endothelial transcriptional control of plasmin activity and sterile inflammation and reveal their detrimental synergy during liver development.

The purpose of this study was to report our cases of umbilical-portal-systemic venous shunt (UPSVS) and to evaluate the utility of fetal magnetic resonance imaging (MRI) to diagnose this rare anomaly. This retrospective study included the fetuses with umbilical-portal venous system anomalies. All the cases were performed at 1.5 T magnetic resonance unit including the steady-state free precession (SSFP) and single-shot fast spin echo (SSFSE) sequences. We analyzed the abnormal anatomical findings by fetal MRI and compared them with the prenatal ultrasound (US). 15 cases with prenatally diagnosed UPSVS based on MRI or US were enrolled. Eight cases were identified by both MRI and US, including umbilical-systemic shunts (n = 3), ductus venosus-systemic shunt (n = 1), intrahepatic portal-systemic shunts (n = 3) and extrahepatic portal-systemic shunt (n = 1). Six cases were only identified by MRI including intrahepatic portal-systemic shunts (n = 5) and ductus venosus-systemic shunt (n = 1). In the remaining single case, prenatal ultrasound findings were suspicious for an intrahepatic portal-systemic shunt, without corresponding fetal MRI abnormalities. Follow-up data were obtained from thirteen patients. Two cases were lost to follow up. Of the thirteen patients undergoing follow-up, two cases of UPSVS were surgically confirmed. Postnatal imaging failed to identify any abnormalities of portal venous system in nine cases. The rest two cases demonstrated normal development and liver function after birth. Umbilical-portal-systemic venous shunt can be diagnosed prenatally via MRI. Fetal MRI can serve as a valuable adjunct to prenatal US and improve the diagnostic accuracy.

Surgical management for aberrant bile ducts at porta in children undergoing laparoscopic and robotic excision of choledochal malformations.

Eltrombopag, a thrombopoietin receptor agonist for aplastic anaemia, can cause hepatotoxicity. It is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 to form an acyl glucuronide metabolite; however, the relationships among serum concentrations of the acyl glucuronide metabolite, UGT1A1 genotypes and hepatotoxicity remain unclear. We examined the serum concentrations of eltrombopag and its acyl glucuronide metabolite, UGT1A1 genotypes and occurrence of hepatotoxicity (abnormal liver function tests or drug-induced liver injury [DILI]) in 104 samples from 42 patients with aplastic anaemia receiving eltrombopag. The concentrations of eltrombopag and its acyl glucuronide metabolite were significantly higher in samples with abnormal liver function than in those with normal liver function (23.0 ± 18.5 vs. 10.6 ± 9.3μg/mL and 6.9 ± 4.5 vs. 2.1 ± 1.2μg/mL, respectively). Receiver operating characteristic (ROC) analysis demonstrated that the concentration of the acyl glucuronide metabolite provided superior predictive accuracy for hepatotoxicity, with a threshold of 4.0μg/mL, compared with eltrombopag (area under the ROC curve, 0.83 vs. 0.68). All patients with DILI had higher concentrations of the acyl glucuronide metabolite than the cutoff value. The incidence of hepatotoxicity differed across UGT1A1 genotype: 43% in extensive metabolizers (EMs), 11% in intermediate metabolizers (IMs) and none in poor metabolizers (PMs). The formation of the acyl glucuronide metabolite was 1.5-fold greater in EMs than in IMs/PMs. These findings suggest that eltrombopag-induced hepatotoxicity is dependent on the concentration of eltrombopag acyl glucuronide and influenced by UGT1A1 genotype, highlighting the potential utility of serum acyl glucuronide monitoring and UGT1A1 genotyping for preventing and managing the hepatotoxicity.

A novel HDAC1-Hcy/Glu-ferroptosis axis underlies valproic acid-induced hepatic steatosis.

The healthy donor effect (HDE) refers to the lower mortality observed among blood donors compared to the general population. While HDE arises due to healthier individuals being more likely to donate, the extent to which it is influenced by genetic differences remains unclear. To elucidate the genetic basis of HDE, we conducted a genome-wide association study (GWAS) involving 53,688 active blood donors with extensive donation histories and 228,060 controls from biobank cohorts within the FinnGen project. We identified 46 fine-mapped genome-wide significant loci associated with several health-related endpoints, plasma protein levels and laboratory measurements. Genetic correlation analyses across FinnGen endpoints revealed that blood donors are genetically protected against several diseases beyond those affecting donation eligibility. Using the correlated endpoints as exposures in multivariable Mendelian randomization (MVMR) to inform priors for Bayesian GWAS, we found that 25 of the fine-mapped loci exert a direct effect on blood donorship (BD) rather than acting through disease mediation, suggesting a genetic contribution to maintaining a health state conducive to long-term donation. We also performed MVMR analyses of laboratory traits. The results indicated that normal liver function, blood glucose, and low inflammation independently increase the likelihood of becoming a blood donor, while iron levels showed no causal relationship. Functional enrichments among the proteins regulated by the 46 fine-mapped variants included mainly red cell antigen-related cell adhesion processes. In conclusion, our findings demonstrate that HDE is partly explained by genetic factors, involving both direct health-promoting effects and indirect eligibility selection.

In pediatric liver transplantation (pLT), follow-up liver biopsies (fLBs) frequently reveal subclinical histological abnormalities, despite normal liver function tests. Findings, including inflammation, fibrosis, and immune-mediated changes, suggest overlapping alloimmune and autoimmune mechanisms with potential long-term consequences. We performed a prospective, single-center cohort study at the Vall d'Hebron Barcelona Hospital Campus, including 167 children who underwent 299 liver biopsies (214 protocol, 85 post-immunosuppression modification) from 2018 to 2024. Immunosuppression was adjusted according to a preestablished histology-guided protocol, intensifying therapy in patients with subclinical T cell-mediated rejection (S-TCMR; Banff Rejection Activity Index ≥2) detected in protocol biopsies. S-TCMR was identified in 71 of 214 (33.2%) protocol biopsies, with fibrosis (Ishak ≥2) in 38 (53.5%). Following protocol-driven immunosuppressive intensification, 57 of 71 (80.3%) achieved S-TCMR resolution at 12 mo, with 8 of 12 showing further improvement at 24 mo. Fibrosis regressed by ≥1 Ishak stage in 21 of 38 (55.3%). Autoantibody responders showed superior S-TCMR (P = 0.006) and fibrosis outcomes (P = 0.05). Donor-specific antibody-positive patients exhibited lower S-TCMR resolution (odds ratio [OR], 3.3; P = 0.1) and a higher risk of persistent fibrosis (OR, 4.8; P = 0.03). Plasma cell-rich S-TCMR (18/71 [25.4%]) strongly correlated with C4d deposition (5-fold increase) and markedly reduced fibrosis regression (OR, 11.0; P < 0.001), indicating resistance to standard immunosuppression. Histology-guided, protocol-driven immunosuppression intensification effectively reversed most S-TCMR and fibrosis, underscoring the importance of long-term protocol biopsies for individualized therapy in pLT.

Precisely map and ablate the aortorenal ganglion (ARG) using noninvasive ultrasound technology to evaluate therapeutic effects and mechanisms in hypertension and related organ involvement. A noninvasive dual-frequency ultrasound with a 3-dimensional targeting system was utilized to precisely map and ablate the ARG in a hypertensive canine model (2-kidney, 1-clip). Blood pressure changes from ultrasound stimulation served as a real-time evaluation metric, leading to an ultrasound stimulation-ablation-re-stimulation-supplementary ablation protocol for comprehensive ablation. Follow-up assessments at 1, 3, and 6 months post-ablation included evaluations of blood pressure, ventricular fibrosis and hypertrophy, cardiac function, and both local and systemic sympathetic nerve activity. One month postultrasound-targeted ARG ablation, there was a significant reduction in systolic blood pressure (∆ = -8.67±2.07 mm Hg; P<0.05), with further decreases at 3 months (∆ = -14.17±3.49 mm Hg; P<0.001) and 6 months (∆ = -24.83±4.49 mm Hg; P<0.001). Histological and echocardiographic assessments indicated improvements in ventricular fibrosis and hypertrophy, along with an enhanced left ventricular ejection fraction. Moreover, a reduction in sympathetic nerve activity was observed in the body, heart, and kidneys. In addition, aortic and adrenal tissue integrity, as well as normal liver and kidney functions, with no significant differences between the hypertension model and ARG ablation groups were observed. Ultrasound-targeted ablation of the ARG significantly reduces blood pressure, suppresses sympathetic nerve activity in the systemic, cardiac, and renal regions, and alleviates hypertension-induced ventricular remodeling, offering a promising therapeutic strategy for hypertension and related cardiovascular diseases.

Hepatic management of toxic sterols after acute deletion of Cyp51 from cholesterol synthesis.

Background and Objectives: Severe burn injuries are still associated with high mortality. The length of intensive care stay is strongly influenced by the severity of organ failure, with multi-organ failure being the main cause of death in up to 40% of cases. Liver dysfunction is the second most common organ failure. Conventional diagnosis relies on static laboratory parameters that reflect damage already caused. Measuring the hepatic clearance of indocyanine green (LiMON®) offers a dynamic, bedside method for detecting liver dysfunction early, enabling timely therapy adjustments. Materials and Methods: In this prospective single-centre observational study, all patients admitted to the Unfallkrankenhaus Berlin Burns Centre from October 2022 to September 2024 with ≥30% TBSA burns were included. Liver function was assessed via LiMON® within 24 h post-injury and every 48 h until day 14 or ICU discharge. Static liver parameters were measured in parallel. Results: We included a total of 23 patients. An initial measurement was only successful in 18 cases. On admission, six patients (33%) had normal liver function with a plasma duration rate (PDR) > 18% (PDR 30.9 ± 7.3%), while 12 (67%) showed reduced clearance (PDR 14.5 ± 2.6%). In 75% of cases (n = 9), function recovered within 48 h. Based on PDR progression, four liver function patterns were defined: "stable", "recovery", "late insufficiency", and "failure"; a fifth pattern included all patients who were deceased during this study ("death"). These groups differed in fluid therapy, plasma transfusion, and catecholamines administered. PDR correlated well with aminotransferase levels. Conclusions: Dynamic liver function monitoring enables earlier detection of impairment than static markers. Early identification of at-risk patients could guide fluid management and improve outcomes. LiMON® is a valuable tool in burn care, though alternative methods may be needed in patients with severe systemic hypoperfusion.

Perivascular epithelioid cell tumor (PEComa) is a rare liver tumor, with few cases reported in the literature. Clinical decisions regarding patients diagnosed with PEComa are based on studies with small sample sizes. Differential diagnosis between PEComa and other types of liver lesions is challenging due to non-specific radiological findings associated with this type of liver mass. We report the case of a 51-year-old female patient followed at the outpatient hepatology clinic of Patras, General University Hospital, Greece, for chronic hepatitis B. The patient was asymptomatic, with positive hepatitis B surface antigen and normal liver function tests. An area with abnormal echogenicity and a diameter of 28mm was observed in an abdominal ultrasound during routine follow up. Magnetic resonance imaging (MRI) was performed, and a mass with a diameter of 30.6mm was found on surgical liver segment IV. A follow-up MRI 8months later showed the lesion had increased to 36mm and exhibited suspicious radiological characteristics. Surgical excision of liver segment IV was performed. Post-surgical pathological analysis of the tumor confirmed a diagnosis of PEComa, with no evidence of vascular or lymphatic invasion. The low mitotic index, the size of the tumor and the lack of nuclear atypia or diffuse pleomorphic morphology supported a favorable tumor behavior. In conclusion, PEComas are rare liver tumors without pathognomonic radiological features. Surgical excision of these masses is the safest treatment option, and post-surgical pathological analysis is essential for the diagnosis and prognosis of these patients.

BACKGROUND Torsion of the falciform ligament fatty appendage is a rare subset of intra-abdominal fat infarction. Fewer than 20 cases have been reported in the literature to date. Clinical and laboratory findings are non-specific, making imaging essential for diagnosis and management. CT typically shows a fat-density lesion with surrounding inflammatory changes along the falciform ligament, which is diagnostic. Recognizing this rare entity can prevent unnecessary surgical exploration. CASE REPORT We present 2 cases: a 47-year-old Chinese woman and 32-year-old Chinese man with right upper-abdominal and epigastric pain, respectively. Associated symptoms such as nausea, non-bilious vomiting and anorexia were reported. On clinical examination, tenderness was elicited upon palpation without guarding. Laboratory tests were unrevealing, with normal liver function and lipase markers. In view of persistent abdominal pain in both cases, a CT abdomen and pelvis was performed, which showed inflammatory changes along the course of the falciform ligament, suggestive of torsion of the falciform ligament fatty appendage. Both patients were subsequently managed conservatively and discharged in good condition several days later. CONCLUSIONS Torsion of the falciform ligament fatty appendage is a rare but important cause of right upper-abdominal or epigastric pain. By discussing the clinical presentation, imaging findings, and treatment options of this condition, we aim to raise awareness of this pathology as a potential differential diagnosis for such pain.

Severe acute respiratory syndrome coronavirus 2-induced encephalitis in children poses significant challenges due to neurological sequelae and mortality. We present two pediatric cases of coronavirus disease 2019 (COVID-19) encephalitis treated with integrated Western and traditional Chinese medicine (TCM). The two patients, aged 8 and 10, diagnosed with COVID-19 encephalitis, received immediate integrated care with Western and TCM upon admission to our hospital. Both patients exhibited marked clinical improvement within 4 days of integrative treatment and were discharged after 8 days. Upon discharge and follow-up visits, both patients were alert, with normal electroencephalography examinations, and exhibited normal liver and kidney function without significant adverse effects. This suggests the potential clinical benefit of integrating Western and TCM in treating COVID-19 encephalitis and suggests its potential effectiveness for other viral or bacterial encephalitis.

BackgroundMetabolic (dysfunction)-associated fatty liver disease (MAFLD) is the most common chronic liver disorder in children and adolescents, with its prevalence rising alongside the global childhood obesity epidemic. Liver function indicators offer a potential non-invasive screening alternative, but existing evidence on their association with pediatric MAFLD is inconsistent due to heterogeneous study designs and populations. Therefore, this systematic review and meta-analysis aimed to synthesize global evidence to definitively evaluate liver function indicators as risk factors for MAFLD in children and adolescents.MethodsFour databases—The Cochrane Library, Embase, Web of Science, and PubMed—were searched from inception to July 5, 2025. The eligible studies were observational in design and focused on children and adolescents (<18 years), comparing MAFLD prevalence/risk between those with abnormal versus normal liver function indicators. Two independent researchers performed literature screening, information collection, and quality evaluation per the eligibility criteria. The ‘meta’ package in R was adopted to compute the odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between liver function indicators and MAFLD. Heterogeneity and publication bias were also assessed.ResultsThis meta-analysis incorporated 27 studies, involving 3,237 confirmed MAFLD cases. Levels of alanine aminotransferase (ALT) [OR (95% CI): 1.15 (1.01, 1.30)], gamma-glutamyl transferase (GGT) [1.30 (1.09, 1.56)], and high-density lipoprotein (HDL) [0.97 (0.96, 0.98)] were associated with MAFLD risk. Elevated ALT [OR (95% CI): 20.63 (2.39, 178.09)], total cholesterol (TC) [3.36 (1.15, 9.82)], triglycerides (TG) [4.86 (2.37, 9.98)], low-density lipoprotein (LDL) [3.74 (1.15, 12.19)], and decreased HDL [2.77 (1.97, 3.91)] were identified as potential risk factors for MAFLD in children and adolescents. Overall, subgroup analyses (by confounder adjustment status and study design), sensitivity analyses, and meta-regression did not identify potential sources of heterogeneity. No significant publication bias was observed.ConclusionsLiver function indicators show promise as screening tools for the early detection of MAFLD susceptibility. This study has several limitations, including a small number of included studies, resulting in heterogeneity, as well as the inherent risk of bias (ROB) in observational designs and the imprecision of some results.

Epstein-Barr virus (EBV) frequently causes temporary liver injury during initial infection, and in severe cases, fulminant hepatitis and liver failure can occur. This study aimed to examine the expression of key Absent in Melanoma 2 (AIM2)-pathway pyroptosis mediators (AIM2, Caspase-1, Gasdermin D[GSDMD], IL-1β, and IL-18) in the blood of children experiencing primary EBV infection and to assess their correlation with viral load and liver injury. Sixty-five children hospitalized with primary EBV infection were enrolled and categorized based on liver function (Abnormal Liver Function, n = 35; Normal Liver Function, n = 30). Control groups included 30 healthy children with past EBV infection and 30 healthy seronegative children. Real-time reverse transcription polymerase chain reaction was used to detect the mRNA expression levels of AIM2, Caspase-1, and GSDMD. IL-1β and IL-18 serum concentrations were measured by enzyme-linked immunosorbent assay. The institutional clinical laboratory was responsible for routine biochemical indicators, including EBV-DNA load. The study indicated that children with primary EBV infection exhibited significantly elevated mRNA expression of AIM2, Caspase-1, and GSDMD, alongside increased serum IL-1β and IL-18 concentrations, compared to both control groups. Within the primary infection group, serum EBV-DNA load showed positive correlations with these pyroptosis markers. Furthermore, patients with primary EBV infection and abnormal liver function had significantly higher levels of these mediators than infected patients with normal liver function. AIM2 mRNA expression also positively correlated with Caspase-1 mRNA, GSDMD mRNA, IL-1β, and IL-18 levels. AIM2-dependent pyroptosis is implicated in the systemic inflammatory response to EBV and may contribute to the immunopathogenesis of EBV-associated hepatitis.

Cisplatin (CIS) is a highly effective chemotherapeutic agent widely used to treat solid tumors. However, its clinical use is significantly limited by dose-dependent hepatotoxicity, characterized by hepatocellular injury and apoptosis. Despite extensive research efforts, an effective pharmacological strategy to reduce CIS-induced liver dysfunction remains elusive. Sacubitril/valsartan (VS), an angiotensin receptor-neprilysin inhibitor, has shown cytoprotective and anti-apoptotic effects in various models of organ toxicity. However, its ability to protect against CIS-induced liver damage has not been thoroughly studied. This research aimed to assess the hepatoprotective potential of VS in rat models of cisplatin-induced liver toxicity, focusing on oxidative markers including reactive oxygen species (ROS) and malondialdehyde (MDA), as well as the roles of caspase-3 inhibition and modulation of retinoid X receptor-alpha (RXR-α) in its mechanism. In this study, adult male Wistar rats were randomly assigned to four groups: control, VS-treated, cisplatin-treated, and CIS + VS co-treated. Hepatotoxicity was induced by administering cisplatin at 8mg/kg via intraperitoneal injection, repeated over three cycles. Meanwhile, VS was given orally at 60mg/kg daily for 10 days. Liver biochemical markers, including ROS, MDA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), total bilirubin (TBIL), and lactate dehydrogenase (LDH), were measured using ELISA. Liver tissue was examined histologically with hematoxylin and eosin staining, and the expression of caspase-3 and RXR-α was evaluated through immunofluorescence. Cisplatin administration significantly increased ROS, MDA, ALT, AST, ALP, TBIL, and LDH levels, while decreasing TP and ALB, indicating severe liver dysfunction. Histopathology showed extensive hepatocellular degeneration, necrosis, and inflammation. Co-treatment with VS significantly normalized liver function tests, improved protein levels, and maintained normal liver histology. Additionally, VS markedly reduced caspase-3 immunoreactivity while increasing RXR-α expression compared to CIS alone. Sacubitril/valsartan appears to protect the liver from cisplatin toxicity, primarily by inhibiting oxidative stress and apoptosis through caspase-3 suppression, and modulating RXR-α signaling. These results provide new insights into the mechanisms involved and suggest that VS may be a promising adjunct therapy to lessen cisplatin-induced hepatotoxicity during chemotherapy.

Acetaminophen overdose is a leading cause of drug-induced acute liver damage, underscoring the urgent need for accessible hepatoprotective therapies. This study evaluated the hepatoprotective effects of Aqueous Aloe vera gel extract on acetaminophen-induced liver damage in adult male Albino Wistar rats. Liver Damage was induced in Albino Wistar rats by oral administration of acetaminophen (750mg/kg). The rats were divided into six groups: normal control, negative control, positive control (silymarin 50mg/kg), and three treatment groups receiving Aloe vera gel extract at doses of 250mg/kg, 500mg/kg, and 1000mg/kg. Body and liver weight, hematological, biochemical and oxidative stress parameters and liver histology were assessed after 7days of treatment. Treatment with Aloe vera gel extract demonstrated dose-dependent hepatoprotective, anti-inflammatory and antioxidant effects with the 1000mg/kg dose exhibiting efficacy comparable to silymarin. Higher doses (1000mg/kg) significantly increase both the body weight and weight of the liver (p = 0.0265 and p = 0.0061); decreased the white blood cell count (p = 0.0034) and also improved hematological parameters. The extract at 1000mg/kg also enhanced antioxidant status by reducing MDA levels (p < 0.0001) while increasing SOD (p < 0.0001) and catalase activities. Histological examination also showed that higher doses of the aqueous Aloe vera gel extract restored liver histoarchitecture, with clearly defined nuclei and cell borders. This study demonstrates that the aqueous Aloe vera gel extract mitigates acetaminophen-induced hepatotoxicity through antioxidant, anti-inflammatory, and regenerative mechanisms. At 1000mg/kg, it restored hepatic histoarchitecture, haematological homeostasis, normalized liver function biomarkers, and suppressed oxidative stress, rivalling silymarin in efficacy. The observed improvements in liver histology, haematological parameters, and antioxidant biomarkers indicate Aloe vera's therapeutic potential, likely mediated through its bioactive constituents with antioxidant and anti-inflammatory properties. Further research is recommended to understand its mechanism of action, long-term and potential clinical applications.

Lurasidone is an antipsychotic drug used to treat schizophrenia and bipolar depression, primarily metabolized by cytochrome P450 3A4 (CYP3A4). Its pharmacokinetics (PK) can vary depending on CYP3A4 genetic polymorphisms and liver function, often requiring clinical dose adjustments. However, there is a lack of systematic tools for quantitatively predicting such interindividual variability. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of lurasidone that incorporates CYP3A4 polymorphisms and hepatic impairment to support dose optimization across clinical populations. The PBPK model was constructed using published in vitro and clinical PK data. Model validation was performed by comparing simulations with independent clinical trials. We conducted single- and multiple-dose simulations reflecting CYP3A4 genotype (wild-type vs. *15 allele) and hepatic impairment (Child-Pugh A, B, C). Predicted exposures were compared with a reference population (CYP3A4 wild-type, normal liver, 80 mg/day) to explore dose adjustment needs. Simulation results demonstrated increased exposure with worsening liver function, and decreased exposure in the presence of the *15 allele due to enhanced metabolism. Based on these results, reduced doses (20-40 mg/day) were recommended for wild-type patients with hepatic impairment, while higher doses (up to 240 mg/day) were needed for *15 carriers with normal liver function. Adjusted doses resulted in stable therapeutic exposures across groups. This PBPK model offers a quantitative strategy for individualizing lurasidone dosing based on genotype and hepatic function. It provides a valuable precision dosing tool to ensure safety and efficacy in vulnerable patient populations.