Autoimmune hepatitis (AIH) is an inflammatory autoimmune disease of the liver. Oxidative stress triggered by reactive oxygen radicals is a common pathophysiological basis for the pathogenesis of many liver diseases, and ferroptosis is associated with the toxic accumulation of reactive oxygen species. The signaling transduction pathways responsible for iron processing and lipid-peroxidation mechanisms are believed to drive ferroptosis. However, the specific mechanisms regulating ferroptosis remain unclear. The aims of this investigation were to identify the possible effector functions of ferroptosis, based on glutathione peroxidase 4 (GPX4) regulation in an S100-induced autoimmune hepatitis mouse model and hepatocyte injury models. The S100 liver antigen-induced AIH mouse model was used to detect ferroptotic biomarkers using western blotting. Upregulated levels of cyclooxygenase2 (COX2) and Acyl-Coenzyme A synthase long-chain family member 4 (ACSL4) were observed in the S100-induced AIH model group, while levels of GPX4 and ferritin heavy chain 1 (FTH1) were downregulated ( P < 0.05 ). The expression profiles of COX2, ACSL4, GPX4, and FTH1 were restored following the administration of ferrostatin-1. In addition, Nrf2 and HO-1 levels in the S100-induced AIH model mice after treatment with ferrostatin-1 were downregulated compared to the nonferrostatin-1-treated S100-induced AIH model mice ( P < 0.05 ). Moreover, COX2 and ACSL4 levels were significantly upregulated, with significant FTH1 downregulation, in the AIH model mice when liver-specific GPX4 was silenced using AAV8 constructs. These data indicate that inhibition of ferroptosis significantly ameliorated the influence of AIH on the Nuclear factor E2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway, and that ferroptosis may act as an initiator or intermediate mediator leading to AIH.

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Autoimmune hepatitis (AIH) is a progressive and chronic inflammatory disease in the liver. MARCO is a surface receptor of macrophage involving in tissue inflammation and immune disorders. Moreover, polyguanine (PolyG) is considered to bind to macrophage receptor with collagenous structure (MARCO). However, the role of MARCO and PolyG in the development and treatment of AIH still remains unclear. Therefore, this study explores the expression of MARCO and therapeutic activity of PolyG in both S100-induced AIH in mouse and Lipopolysaccharide (LPS)-treated macrophage (RAW264.7 cells). Moreover, there were significant increases in inflammatory factors and MARCO, as well as decrease in I-kappa-B-alpha (Ik-B) in the liver of AIH mice and LPS-induced cells. However, PolyG treatment significantly reversed the elevation of inflammatory cytokins, MARCO and reduction of Ik-B. In addition, PolyG treatment could downregulate the expression of Toll-like receptor 4 (TLR4) and TIR-domaincontaining adaptor inducing interferonβ (TRIF), decrease macrophage M1 polarization and increase macrophage M2 polarization. When hepatocytes were co-cultured with different treatment of macrophages, similar expression profile of inflammatory cytokines was observed in hepatocytes. The research revealed that MARCO expression was elevated in AIH mice. PolyG treatment and inhibition of MARCO significantly reduced inflammatory cytokines expression in the liver as well as hepatocytes and macrophages. Therefore, MARCO could be a target for the treatment of AIH.

Objective:To investigate liver histologic disease in chronic hepatitis B (CHB) patients with normal ALT (<40U/L), as well as to evaluate the potential benefits of antiviral therapy for these patients, and to establish a management strategy for them. Methods:We retrospectively examined 1352 patients who underwent liver biopsy from 2017 to 2021 and then obtain their 1-year follow up data to establish a predict model of 1-year HBVDNA clearance rate through Logistic regression. Results:The proportion of patient with significant histological disease (significant liver necroinflammation or fibrosis) in the high nALT group was significantly higher than that in the low nALT group (56.43% vs 43.82%, p < 0.001, Table 1). HbeAg negative, GGT and ALT value (OR 0.024, 95% CI 0.011–0.055, p < 0.001; OR 1.027, 95% CI 1.006–1.050, p = 0.013; OR 1.993,95% CI 1.115–3.560, p = 0.020, Table 4) were independent predict factors. High normal ALT is an indicator of 1-year HBVDNA clearance after antiviral treatment. Conclusion: CHB patients with high-normal ALT have significantly higher histological disease rates, and these patients may benefit better from antiviral therapy. We suggest should undergo histological evaluation of liver disease as soon as possible. We also propose these patients should be offered antiviral therapy when feasible.