BACKGROUND:Statins are widely prescribed for cardiovascular risk reduction and are generally well tolerated. However, they can cause drug-induced liver injury (DILI), and the genetic factors contributing to statin-DILI remain poorly understood. METHODS:HLA association and genome-wide association (GWAS) studies were conducted to identify genetic variants associated with statin-DILI. High-confidence cases (n=71) were identified from the Drug-Induced Liver Injury Network (DILIN) and compared with statin-exposed controls without liver injury (n=551) from the Indiana Biobank. Association testing was performed across ancestries and within ancestry, adjusting for age, sex, and three principal components of genotypes. Top variants were further evaluated in non-statin DILI cases and unexposed controls. In addition, we investigated the frequency of candidate variants among a comprehensive list of pharmacogenetic variants related to statins. RESULTS:HLA-DQA1*03:01 was significantly associated with increased risk of statin-DILI (OR=3.49, 95% CI 2.21-5.51, p-value=1.27×10-7), with enrichment observed across multiple ancestry groups, particularly non-Hispanic Black and Hispanic individuals. From the GWAS, three loci showed suggestive associations (p-value <5×10-06) with statin-DILI, including rs35197737 in RGS1 (OR=5.03, 95% CI 1.11-3.66, p=1.14×10-7), rs75629598 in FRMD4A (OR=4.4, 95% CI=2.33-8.12, p=3.97×10-6), and rs7658630 in the intergenic region on chromosome 4 (OR=4.86, 95% CI 2.66-8.85, p=2.68×10-7). No pharmacogenetic variants revealed statistical significance. CONCLUSION:We identified HLA and non-HLA genetic variants associated with statin DILI. Future studies with larger sample sizes should confirm these observations.
BACKGROUND:Alcohol-associated liver disease (ALD) is a major global health condition characterized by inflammation, hepatocellular injury, fibrosis, and impaired liver regeneration. To capture key features of severe ALD, we employed a murine model combining ethanol (EtOH) exposure with galactosamine (GalN), a hepatotoxic agent that sensitizes the liver to endotoxin-induced injury. Using this model, we evaluated the therapeutic efficacy of resolvin D1 (RvD1), a lipid mediator with potent anti-inflammatory and tissue-protective actions. METHODS:C57BL/6J male mice were fed 5% EtOH-containing liquid diet for 10 days and administered GalN (500 mg/kg, i.p.) on days 9, 10, and 11, followed by a single EtOH binge (5 g/kg) on day 11. A separate cohort also received RvD1 (500 ng/mouse, days 7-12) as a therapy. Markers of endotoxemia, liver injury, inflammation, fibrosis, and regeneration were evaluated at 9 and 48 hours after the binge. RESULTS:The EtOH+GalN model reproduced hallmark features of advanced ALD, including acute liver injury, sustained inflammation, induction of pro-fibrotic gene markers, reduced hepatic synthetic function, and markedly impaired regenerative capacity. RvD1 treatment significantly mitigated EtOH+GalN-induced pathology, lowering plasma endotoxin and ALT levels, reducing hepatic necrosis, and limiting neutrophil infiltration. RvD1 also decreased hepatic IL-6 levels at 9 hours and reduced IFN-γ at 48 hours. In addition, RvD1 attenuated the expression of pro-fibrotic genes and improved the diminished regenerative response in EtOH+GalN-treated mice, increasing hepatocyte proliferation at 48 hours and partially restoring plasma albumin concentrations. CONCLUSION:This study established an EtOH+GalN exposure mouse model of severe ALD and demonstrated that RvD1 exerts significant hepatoprotective effects. The findings support RvD1 as a promising therapeutic candidate for advanced ALD and provide the rationale for further mechanistic studies and translational evaluation.
BACKGROUND:Acetaminophen (APAP) is a widely used analgesic and antipyretic agent that is safe at therapeutic doses. However, due to its extensive misuse, APAP-induced liver injury has become a major public health concern. Although mesenchymal stem/stromal cells (MSCs) represent a promising emerging therapy for APAP-induced liver injury, considerable research has focused on enhancing their efficacy, notably through genetic modification. Fibroblast growth factor 21 (FGF21), an endocrine hormone activated by metabolic stress, is known to regulate energy homeostasis, glucose and lipid metabolism, and to promote the homing of MSCs to sites of injury. Consequently, this study was designed to determine whether genetically engineering MSCs to overexpress FGF21 (FGF21-MSCs) augments their therapeutic potential against APAP-induced acute liver injury (ALI). METHODS:In this investigation, MSCs were employed as a platform for FGF21 gene delivery. The MSCs were transduced with lentiviral vectors encoding the FGF21 gene to facilitate sustained FGF21 overexpression. We subsequently assessed the therapeutic potential of these FGF21-MSCs in a murine model of APAP-induced ALI. The extent of liver injury was comprehensively evaluated. Furthermore, the underlying mechanisms were elucidated using techniques including immunohistochemistry, immunofluorescence, and flow cytometry. RESULTS:Our results demonstrated that FGF21-MSCs significantly enhanced the therapeutic efficacy of conventional MSCs against APAP-induced ALI via a biphasic mechanism: attenuating oxidative stress and inflammation during the acute injury phase, while actively fostering tissue repair during the subsequent regenerative phase. This protective effect is primarily mediated through the enhancement of macrophage phagocytic capacity, thereby accelerating tissue repair and regeneration. CONCLUSIONS:Our findings demonstrate that FGF21-MSCs significantly augment therapeutic efficacy against APAP-induced ALI in mice, thereby yielding critical insights and revealing novel therapeutic targets for ALI prevention and treatment.
BACKGROUND:Patient-reported outcome measures (PROMs) are increasingly incorporated into hepatology research, yet few have been rigorously evaluated, particularly among patients with decompensated cirrhosis. The Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) captures multidimensional liver disease-specific burden, while the disease-agnostic PROMIS-29 assesses physical and mental health broadly. We evaluated the performance of FACT-Hep and its relationship to PROMIS-29 among participants with cirrhosis or hepatocellular carcinoma (HCC) enrolled in a prospective multicenter clinical trial. METHODS:Baseline data were analyzed from 935 participants enrolled in the PAL LIVER trial. This study enrolled patients with Child-Turcotte-Pugh (CTP) B/C cirrhosis and/or with HCC. Health-related quality of life (HRQoL) was assessed using FACT-Hep and PROMIS-29. Correlations and multivariable linear regression models examined associations between PROM scores and clinical characteristics. RESULTS:Among 935 patients, the mean FACT-Hep total score was 116 (SD 28.16), with worse scores among women, young participants (age <50 y), and Whites (all p<0.05). Patients with CTP B/C cirrhosis (83%) had worse HRQoL than those with HCC alone (28%) (p<0.0001). Younger age, higher MELD 3.0, smoking, and worse ECOG status were independently associated with total FACT-Hep score. FACT-Hep correlated with PROMIS preference scores (correlation coefficient=0.78). MELD 3.0 demonstrated a stronger association with total FACT-Hep score than with PROMIS measures. CONCLUSIONS:HRQoL measures provide important information distinct from disease severity indices. HRQoL impairment in patients with advanced chronic liver disease is driven primarily by decompensation, particularly ascites and hepatic encephalopathy. FACT-Hep and PROMIS-29 correlate well. FACT-Hep is a valid measure and effectively captures the multidimensional liver disease-specific burden. PROMIS-29 measures broader aspects that may be influenced by many factors beyond liver disease.
Background: Alcohol-associated liver disease (ALD) is a leading cause of advanced liver disease and liver transplantation worldwide. Cardiometabolic risk factors (CMRFs) may worsen ALD prognosis. While recent nomenclature acknowledges the impact of CMRFs in steatotic liver disease with low-to-moderate alcohol use, individuals with high alcohol intake are still classified as having ALD regardless of CMRF status. We conducted a systematic review to evaluate the impact of CMRFs, primarily diabetes, obesity, and metabolic syndrome, on clinical outcomes in patients with ALD. Methods: We performed a systematic review of peer-reviewed studies published through October 21, 2025, as well as abstracts from the AASLD, EASL, DDW, ACG, and APASL conferences from 2023 to 2025. We included studies involving adults (≥18 y) with ALD that assessed at least one CMRF (eg, diabetes, obesity, metabolic syndrome) and reported longitudinal clinical outcomes. Primary outcomes included incident cirrhosis, hepatocellular carcinoma (HCC), overall and cause-specific mortality, cardiovascular events, liver-related complications, and liver transplantation. Results: Nineteen studies comprising 132,054 patients with ALD met the inclusion criteria. Diabetes was consistently associated with increased risks of overall mortality [adjusted hazard ratio (aHR) 3.00], liver-related mortality (aHR 3.60), HCC (hazard ratios 1.6–21.7), and cardiovascular mortality (aHR 19.91). Elevated BMI was linked to higher all-cause mortality (aHR 1.16–1.58), cardiovascular mortality (aHR 3.76), HCC incidence (HR 2.0–2.9), and liver-related mortality (aHR 16.22). Metabolic syndrome was associated with increased overall (HR 1.27–2.37) and liver-related mortality (HR 1.47–2.06). A greater burden of CMRFs was correlated with lower transplant-free survival and reduced rates of hepatic recompensation. Conclusion: Diabetes, obesity, and metabolic syndrome are associated with worse hepatic and extrahepatic outcomes in ALD.
