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.

Prognostic scores are valuable tools for predicting survival in patients with chronic liver disease. Recently, the albumin-bilirubin (ALBI) score has emerged as a potential prognostic indicator in liver-related conditions. This study aimed to compare the prognostic efficacy of the ALBI score with the Model for End-stage Liver Disease (MELD), MELD-Na+, and Child-Turcotte-Pugh (CTP) scores in predicting survival among patients with alcohol-associated liver disease (ALD).

This study included consecutive ALD patients admitted to the Medicine and Gastroenterology wards of MKCG Medical College and Hospital, Berhampur, Odisha, India, between November 2019 and November 2022. Upon hospitalization, baseline characteristics, clinical and laboratory parameters, ALBI, MELD, MELD-Na+, and CTP scores were recorded. The accuracy of these scores in predicting survival up to three years was compared.

A total of 490 ALD patients were included. Higher ALBI scores were observed in patients who died during hospitalization (p < 0.001), at 28 days (p < 0.001), 90 days (p < 0.001), six months (p < 0.001), one year (p < 0.001), two years (p < 0.001), and three years (p < 0.001), compared to those who survived. However, the area under the receiver operating characteristic (AUROC) curves showed that the ALBI score was inferior to MELD, MELD-Na+, and CTP scores in predicting survival at admission [AUROC: ALBI (0.719), MELD-Na+ (0.823), MELD (0.817), CTP (0.770)] and at three years [AUROC: ALBI (0.755), MELD-Na+ (0.787), MELD (0.758), CTP (0.784)]. Furthermore, Cox regression analysis revealed that components used in the MELD, MELD-Na+, and CTP scores—such as serum creatinine, serum sodium, and hepatic encephalopathy—were independent predictors of mortality, whereas the components of the ALBI score (serum albumin and serum bilirubin) were not.

All hospitalized ALD patients had a grade 3 ALBI score, with significantly higher scores observed among non-survivors compared to survivors. However, MELD, MELD-Na+, and CTP scores were superior to the ALBI score in predicting survival both during hospitalization and over a three-year follow-up period.

The causal biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) and their clinical value remain unclear. In this study, we aimed to identify biomarkers for MASLD and evaluate their diagnostic and prognostic significance.

We conducted a Mendelian randomization analysis to assess the causal effects of 2,925 molecular biomarkers (from proteomics data) and 35 clinical biomarkers on MASLD. Mediation analysis was performed to determine whether clinical biomarkers mediated the effects of molecular biomarkers. The association between key clinical biomarkers and MASLD was externally validated in a hospital-based cohort (n = 415). A machine learning–based diagnostic model for MASLD was developed and validated using the identified molecular biomarkers. Prognostic significance was evaluated for both molecular and clinical biomarkers.

Six molecular biomarkers—including canopy FGF signaling regulator 4 (CNPY4), ectonucleoside triphosphate diphosphohydrolase 6 (ENTPD6), and major histocompatibility complex, class I, A (HLA-A)—and eight clinical biomarkers (e.g., serum total protein (STP)) were identified as causally related to MASLD. STP partially mediated the effect of HLA-A on MASLD (23.61%) and was associated with MASLD in the external cohort (odds ratio = 1.080, 95% confidence interval: 1.011–1.155). A random forest model demonstrated high diagnostic performance (AUC = 0.941 in training; 0.875 in validation). High expression levels of CNPY4 and ENTPD6 were associated with the development of and poorer survival from hepatocellular carcinoma. Low STP (<60 g/L) predicted all-cause mortality (HR = 2.50, 95% confidence interval: 1.22–5.09).

This study identifies six causal molecular biomarkers (e.g., CNPY4, ENTPD6, HLA-A) and eight clinical biomarkers for MASLD. Notably, STP mediates the effect of HLA-A on MASLD and is associated with all-cause mortality.

Liver fibrosis is a pathological process resulting from various chronic liver injuries that lead to the formation of liver fibrous scars. It can further progress to cirrhosis and even liver cancer. Currently, there are no effective drugs specifically approved for the treatment of liver fibrosis; etiological therapy remains the main treatment strategy. Therefore, it is necessary to develop anti-fibrotic drugs targeting different pathways involved in liver fibrosis. Transforming growth factor-beta (TGF-β) is a key driver of fibrosis, and targeting TGF-β can effectively reduce liver fibrosis. In this review, we discussed the anti-liver fibrosis effects of TGF-β inhibitors through different signaling pathways, including the application of certain active ingredients from Traditional Chinese Medicine.