Autoimmune hepatitis (AIH) is a progressive chronic liver disease characterized by elevated serum transaminases, production of autoantibodies, hypergammaglobulinemia, and characteristic histological changes in liver, including interface hepatitis and infiltration of plasma cells in the portal area [1]. If not treated in a timely manner, it can rapidly progress to liver cirrhosis. Studies have shown that the incidence of AIH is increasing in the Asia-Pacific region [2], and untreated AIH patients have a mortality rate as high as 56 %. AIH is believed to be the result of interactions between genetic susceptibility, environmental factors, autoimmune responses to self-antigens, dysbiosis of the gut microbiota, and immune regulatory defects [3]. Our previous research has confirmed the close association between AIH progression and disturbances in iron ion metabolism [4], but the specific regulatory mechanisms still need further investigation.

The liver plays a pivotal role in maintaining iron homeostasis, as it is the major site of iron storage and regulation. Hepatocytes are responsible for the uptake, storage, and release of iron. The transferrin receptor on the cell surface recognizes and binds to transferrin protein, allowing the transportation of extracellular iron ions into the cell. This is one of the important pathways for iron uptake by cells. Iron is stored in hepatocytes by binding to ferritin, which consists of light and heavy chains called ferritin heavy chain (FTH) and ferritin light chain (FTL) [5]. Therefore, iron ion metabolism is closely related to these pathways. Abnormal expression of certain iron metabolism-related proteins can disrupt iron homeostasis in the liver, impair normal liver function, and exacerbate disease progression. Emerging evidence suggests a link between iron dysregulation and AIH pathogenesis [6,7]. Studies have demonstrated increased hepatic iron deposition in AIH patients, irrespective of the presence of underlying hereditary hemochromatosis [8]. Given the potential impact of iron dysregulation on AIH progression, targeting iron metabolism has been emerged as a potential therapeutic approach. Iron chelation therapy, commonly used in the treatment of hereditary hemochromatosis [9], has shown promise in reducing hepatic iron levels and improving liver function in AIH patients with iron overload. Furthermore, modulation of hepcidin expression and iron transporters represents a potential strategy to restore iron homeostasis in AIH. Our previous research, as published by the research team, has confirmed significant disturbances in iron metabolism in a ConA-induced AIH mouse model. These disturbances exacerbate hepatic oxidative and nitrosative stress, ultimately leading to iron-mediated hepatocyte ferroptosis [4]. Iron overload may contribute to liver injury and fibrosis in AIH through several mechanisms, including oxidative stress, activation of hepatic stellate cells, and modulation of immune responses ][[6], [10], [11]]. Although there is evident iron dysregulation in AIH, there is currently a lack of in-depth studies exploring how iron ion metabolism is involved in the development of ConA-induced AIH.

STING is a critical immune-regulatory protein highly expressed in macrophages [12], which promotes the polarization of pro-inflammatory macrophages derived from THP-1 monocytes [13]. The protein encoded by the STING gene acts as an intracellular receptor primarily responsible for sensing pathogen infections and cellular abnormalities, initiating immune responses by triggering interferon and other immune-related signaling pathways, playing a crucial role in antiviral and antibacterial defenses [14][15]. When cells detect the presence of bacteria, viruses, or other pathogens, STING is activated, initiating a series of signal transduction pathways that result in the production of type I interferons and other inflammation-related factors [16]. Due to the essential role in immune regulation, researchers have found associations between STING and various immune-related diseases, including autoimmune disorders. Some studies suggest that modulation of STING activity holds promise for developing novel therapeutics for infectious diseases and autoimmune disorders [17]. According to research findings, STING plays a role in causing multi-organ damage during sepsis by facilitating ferroptosis in macrophages through cGAS-STING and independent of interferon signaling. Mechanistically, specific binding sites, namely Q237, E316, and S322, located in the Chitin Binding Domain (CBD) of STING, interact with the coiled-coil domain of NCOA4. This interaction triggers a process called ferritinophagy-mediated ferroptosis, which leads to the exacerbation of the inflammatory response [18]. Additionally, Oroxylin A mediates anti-hepatic fibrosis by enhancing cytokine secretion such as IFN-I through the cGAS-STING pathway to regulate ferritinophagy [19]. Therefore, STING plays a crucial regulatory role in the dynamic balance of iron ions within cells.

In summary, there is a compelling rationale to further explore the role of STING in mediating iron ion metabolism and its impact on the progression of AIH. It is also important to investigate the interactions between STING and other related proteins and pathways, providing new directions for clinical treatment and drug development.