Drug-induced liver injury (DILI) represents a prevalent adverse event associated with medication use. However, the exact mechanisms underlying DILI remain incompletely understood, and the lack of specific diagnostic and prognostic biomarkers poses significant challenges to the clinical diagnosis and treatment of this condition. Consequently, our study aimed to endeavor to identify serum and fecal metabolic biomarkers, enabling more accurate DILI diagnosis and improved prediction of chronic progression.

Untargeted metabolomics analysis was performed on serum and fecal samples obtained from a cohort of 32 DILI patients (causality confirmed via the updated Roussel Uclaf Causality Assessment Method) and 36 healthy controls. Utilizing techniques such as partial least squares-discriminant analysis modeling and t-tests, we identified significantly differentially expressed metabolites and metabolite sets. Causality assessment was performed using the updated Roussel Uclaf Causality Assessment Method.

The findings from the analysis of serum and fecal metabolomics association pathways suggested that perturbations in bile acid metabolism might serve as potential mechanisms underlying the progression of DILI. Our study revealed 22 overlapping differential metabolites between serum and feces, displaying significant concentration differences between the DILI and healthy control groups. Notably, we identified chenodeoxycholic acid and deoxycholic acid as promising markers that not only distinguished DILI patients from healthy individuals but also exhibited predictive potential for DILI chronicity.

The integrated analysis of serum and fecal metabolites uncovers the significant disruption of bile acid metabolites as a key contributing factor in the pathogenesis of DILI. Our study offers promising potential biomarkers for the diagnosis and prognosis of DILI, paving the way for a novel perspective in the realm of DILI diagnosis and treatment.

Emergency department (ED) presentations are associated with higher cancer mortality. This study aimed to investigate the prevalence, frequency, and risk factors in Australian patients diagnosed with malignant skin cancers.

This data-linkage cohort study examined adult patients presenting to the ED at the Royal Melbourne and Western Health hospitals within 12 months of a malignant skin cancer diagnosis. Multivariable logistic and Poisson regressions were used to analyze factors influencing the prevalence and frequency of ED presentations.

A total of 3,873 patients were diagnosed with skin malignancies between 2010 and 2018, of which 631 were diagnosed with melanoma. The prevalence of ED presentation was 29%, representing 2,119 episodes of care (median: 0; range: 0–14). Risk factors for a higher prevalence and frequency included: age ≥75 years (odds ratio (OR) = 1.78 [95% confidence interval 1.47–2.15]; incidence risk ratio (IRR) = 1.52 [1.35–1.70]); male (OR = 1.17 [1.01–1.36]; IRR = 1.23 [1.12–1.35]); socioeconomic status levels of 0–30% (OR = 1.59 [1.24–2.03]; IRR = 1.69 [1.45–1.96]) and 71–100% (OR = 1.30 [1.07–1.58]; IRR = 1.27 [1.12–1.45]); preferred language other than English (OR = 1.47 [1.17–1.84]; IRR = 1.49 [1.32–1.69]); and experience with any systemic therapy or radiotherapy (OR = 3.77 [2.12–6.71]; IRR = 2.36 [1.82–3.05]). Age < 65 years was protective (OR = 0.72 [0.59–0.89]; IRR = 0.78 [0.68–0.90]). Other preferred languages and cancer treatment experience were also risk factors in the sub-cohort with melanoma.

This study reports the prevalence and frequency of ED presentations following a skin cancer diagnosis and their association with socioeconomic and linguistic factors in Australia. Increased awareness of these factors could help address health inequities and potentially reduce the need for ED presentations.

The gut microbiota is crucial in maintaining host health and liver function. Fecal microbiota transplantation (FMT) has shown promising potential in treating chronic liver diseases. To help clinicians quickly master and standardize the clinical application of FMT for chronic liver disease, the Liver Related Digestive Diseases Group of the Chinese Society of Hepatology of the Chinese Medical Association has developed the “Expert Consensus on the Clinical Application of FMT for Chronic Liver Disease.” This consensus addresses the key aspects of FMT, including the indications, contraindications, efficacy, safety, donor selection, transplantation routes, precautions, and the prevention and management of adverse reactions for chronic liver conditions, such as chronic hepatitis, cirrhosis, and liver cancer, thereby offering reference and guidance to clinicians implementing FMT in the treatment of chronic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now the most common chronic liver disease in the Western world, driven by obesity, insulin resistance, and systemic inflammation. Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), can culminate in cirrhosis and hepatocellular carcinoma (HCC). While lifestyle modification remains central to MASLD management, there is growing interest in pharmacological interventions, particularly nutrient-stimulated hormone-based therapies (NuSHs), such as GLP-1 receptor agonists. NuSHs exert metabolic and anti-inflammatory effects primarily via weight loss and improved insulin sensitivity. Emerging clinical data support their efficacy in resolving MASH without worsening fibrosis. However, benefits in cirrhotic patients are less evident, suggesting greater utility in early intervention. Observational studies and clinical trials suggest a reduction in liver-related morbidity with GLP-1 receptor agonist use, though fibrosis regression remains inconsistent. Preclinical models indicate that NuSHs may also reduce MASH-related HCC incidence and tumor burden, likely through systemic metabolic improvements rather than direct antineoplastic action. Observational human data following bariatric surgery reinforce this link, suggesting that weight loss itself plays a key preventive role. Herein, we propose that NuSHs are promising candidates for MASH-related HCC prevention. We provide mechanistic suggestions for how this may occur. Furthermore, incorporating NuSHs into the post-locoregional treatment pathway for HCC may delay the need for systemic anti-cancer therapies, improve immunotherapy synergy and transplant eligibility, and even slow disease progression through reversal of carcinogenic drivers. Future studies are needed to target oncological endpoints and clarify immunometabolic mechanisms to guide the integration of NuSHs into MASLD treatment algorithms.

Skin cancer, the most common global malignancy, is linked to ultraviolet (UV)-driven serum 25-hydroxyvitamin D (25(OH)D)synthesis, with its controversial role possibly reflecting cumulative UV exposure. This study aimed to assess the association and causality between 25(OH)D levels and skin cancer risk using the National Health and Nutrition Examination Survey (1999–2018) data and Mendelian randomization (MR) analyses, evaluating 25(OH)D as a screening biomarker.

We integrated data from the National Health and Nutrition Examination Survey (1999–2018; n = 21,357 U.S. adults, including 631 skin cancer cases) with MR analyses using genome-wide association study-derived genetic variants to assess the causal relationship between serum 25(OH)D levels and skin cancer risk.

Higher 25(OH)D levels were associated with increased risks of nonmelanoma skin cancer [odds ratio (OR) (95% confidence interval (CI)) = 2.94 (2.10, 4.20)], melanoma [OR (95% CI) = 2.94 (1.73, 5.28)], and other skin cancers [OR (95% CI) = 2.10 (1.36, 3.36)]. MR analyses supported a causal relationship for nonmelanoma skin cancer [OR (95% CI) = 1.01 (1.00, 1.02)] and melanoma [OR (95% CI) = 1.00 (1.00, 1.01)]. Risks were highest in males, older adults, and individuals with obesity.

Higher serum 25(OH)D levels are associated with increased skin cancer risk, likely reflecting cumulative UV exposure. Routine monitoring of 25(OH)D, combined with UV exposure management, is recommended for risk stratification in skin cancer screening, particularly among high-risk groups. Validation in multiethnic cohorts is needed to confirm these findings.

Autoimmune hepatitis (AIH) is a severe immune-mediated liver disease with limited treatment options beyond immunosuppressants, which carry significant side effects. Existing evidence suggests that mesaconate (MSA) possesses immunomodulatory properties and may offer advantages over itaconate derivatives by avoiding succinate dehydrogenase inhibition. However, its specific role in AIH remains unclear. This study aimed to investigate the therapeutic effects of MSA on AIH and to elucidate its underlying mechanisms of action.

A murine AIH model was established via tail vein injection of concanavalin A (ConA, 20 mg/kg). MSA (250 mg/kg) was administered intraperitoneally 6 h before ConA exposure. Liver histology, serum transaminase levels, apoptosis markers, oxidative stress markers, and inflammatory cytokines were analyzed to assess the therapeutic efficacy of MSA. Additionally, RNA sequencing and Western blotting were performed to explore the mechanisms of MSA action. In vitro validation was conducted using RAW264.7 macrophages pretreated with MSA (1 mM) followed by interferon-gamma (IFN-γ, 50 ng/mL) stimulation.

MSA pretreatment effectively mitigated ConA-induced AIH by reducing inflammatory responses, oxidative stress, and apoptosis both in vivo and in vitro. The underlying protective mechanism involved MSA-mediated downregulation of IFN-γ expression and subsequent inhibition of the Janus tyrosine kinase 1/2–signal transducer and activator of transcription 1 signaling pathway. The involvement of this pathway in human AIH was also confirmed.

This study provides the first evidence that MSA ameliorates AIH by suppressing the IFN-γ–Janus tyrosine kinase 1/2–signal transducer and activator of transcription 1 signaling pathway, offering novel mechanistic insights and a promising therapeutic candidate for the future treatment of autoimmune disorders.

Portal vein thrombosis (PVT) frequently occurs in patients with porto-sinusoidal vascular disease (PSVD), but its clinical characteristics and outcomes remain poorly understood. This study aimed to investigate the clinical features and outcomes of PVT in PSVD.

A total of 169 patients with PSVD confirmed by hepatic histology were included. PVT was diagnosed using contrast-enhanced magnetic resonance imaging or computed tomography. Demographic, clinical, and laboratory data, portal hypertension-related complications, comorbidities, and mortality were collected and compared between patients with and without PVT. The primary outcomes were baseline clinical characteristics and liver-transplantation-free mortality; the secondary outcome was the dynamic changes of PVT during follow-up.

At baseline, 45 (26.6%) PSVD patients had PVT. Compared to those without PVT, patients with PVT had significantly higher rates of esophageal variceal bleeding (62.2% vs. 29.0%), ascites (73.3% vs. 35.5%), antithrombin III deficiency (78.1% vs. 38.4%) (all p < 0.001), and a history of hematological disorders (11.1% vs. 0.8%, p = 0.005). After a median follow-up of 40.1 (23.4–62.3) months, liver-transplantation-free mortality rates were 7.9% (3/38) and 1.8% (2/112) in patients with and without PVT, respectively (log-rank p = 0.110). Among 41 patients followed for a median of 17.1 (7.4–39.3) months, PVT resolved in 9.1% (1/11) of those with baseline PVT and developed in 13.3% (4/30) of those without PVT at baseline. The one- and two-year cumulative incidence rates of PVT were 3.3% and 6.7%, respectively.

PSVD patients with PVT experience more portal hypertension-related complications, complex coagulation profiles, hematological disorders, and a higher risk of death compared to those without PVT.

Liver failure syndromes are characterised by a dysregulated immune response leading to immune paralysis. Adrenomedullin (ADM) is a potent vasodilator and immunoregulator. This study aimed to explore the role of ADM in liver failure, hypothesising that there is a detrimental imbalance between ADM and adrenomedullin binding protein (AMBP)1 that promotes a switch of monocytes/macrophages towards a pro-restorative phenotype and function.

Consecutive patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF), and decompensated cirrhosis, as well as healthy controls (HC) were included between April 2020 and June 2024. Peripheral blood mononuclear cells/monocytes were isolated and used for RNA sequencing and cell culture. ADM and AMBP1 were measured by enzyme-linked immunosorbent assay.

Fifty-four patients with ALF, 25 with ACLF, 9 with decompensated cirrhosis, and 16 with HC were included. ADM expression in isolated monocytes was increased in ALF (log fold change = 5.88, p = 0.000216413) and ACLF (log fold change = 4.62, p = 0.00057122) compared to HC. Plasma ADM concentration was higher in ALF (1,684 ± 1,156 pg/mL) vs. ACLF (836.1 ± 765.2 pg/mL) and HC (164.8 ± 62.73 pg/mL). AMBP1 was significantly reduced in ALF (59.27 ± 44 µg/mL) vs. ACLF (126.3 ± 72.23 µg/mL) and HC (252.8 ± 159.7 µg/mL) (p < 0.0001, ALF vs. HC). Treatment with LPS increased ADM concentration in peripheral blood mononuclear cell supernatant (ALF n = 6; 561.4 ± 1,038 pg/mL vs. 259.2 ± 213.7 pg/mL, ACLF n = 4; 3,202 ± 491.2 vs. 1,757 ± 1,689 pg/mL). The percentage of CD14+ cells expressing Mer tyrosine kinase was reduced after culture with LPS (2.077 ± 0.87%); however, co-culture with ADM 100 nM restored the phenotype (3.852 ± 1.063%).

ADM is increased in liver failure, whereas AMBP1 is reduced. ADM affects monocyte function, increasing Mer Tyrosine Kinase and promoting a pro-restorative, anti-inflammatory phenotype.

Traumatic brain injury (TBI)-associated cognitive impairment is highly prevalent, severely impacting patients’ daily life and social functioning, with its mechanisms incompletely understood. Globally, TBI affects over 69 million people annually, and post-TBI cognitive impairment may last for years, or even a lifetime, imposing heavy burdens on patients’ families. The brain-lymphatic axis (glymphatic + peripheral lymphatic systems, especially meningeal vessels) has gained attention: glymphatic dysfunction (dependent on astrocyte endfeet Aquaporin-4 polarization, key for clearing β-amyloid and other wastes) causes metabolic waste accumulation and neuroinflammation, while peripheral lymphatic stasis worsens cognitive decline. This review aims to summarize their roles, dissect mechanisms, and outline therapies. The review found that most current studies explore the glymphatic system and the peripheral lymphatic system in isolation, lacking understanding of their dynamic interplay (e.g., bidirectional inflammatory factor transmission, immune cell migration, synergistic dysfunction); longitudinal studies that track axis changes across TBI stages (acute, subacute, chronic) are scarce; diagnostic tools are insufficient (non-invasive biomarkers lack large-scale clinical validation, and imaging has limited clinical use); and existing therapeutic strategies mostly target single subsystems, with few combined interventions for the whole axis. In conclusion, this review highlights critical gaps in current knowledge and proposes integrated, axis-targeted approaches as a promising direction for future research and therapeutic development.

Systemic light chain (AL) amyloidosis is a rare and potentially fatal disease characterized by the abnormal deposition of homogeneous, amorphous amyloid proteins in tissues and organs. This deposition leads to varying degrees of structural and functional abnormalities, ultimately causing organ dysfunction and failure. The disease often involves multiple systems and organs, including the heart, kidneys, gastrointestinal tract, liver, and nervous system, with cardiac and renal involvement being the most common. Due to its rarity, multisystem involvement, and rapid progression, a comprehensive summary of the diagnosis and treatment of AL amyloidosis is crucial for guiding clinical practice and advancing research in this field. This article reviews the progress in diagnosis and discusses future treatment of AL amyloidosis, aiming to provide expanded options for clinical practice.