Protective effect of mesaconate on autoimmune hepatitis via suppression of inflammatory response and oxidative stress

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment. Existing evidence suggests that mesaconate (MSA) exhibits immunomodulatory capacities, however, its role in AIH remains unclear. Here, we constructed a mouse model of AIH by administering concanavalin A (ConA) and conducted prophylactic administration to investigate the pharmacological effect of MSA on AIH and the underlying mechanisms of action. We found that pretreatment with MSA can effectively mitigate ConA-induced AIH by dampening the inflammatory response, oxidative stress, and apoptosis, both in vivo and in vitro. The underlying protective mechanism is associated with the inhibition of the IFN-?-JAK1/2-STAT1 signaling pathway by MSA. Overall, our research not only validates the therapeutic potential of MSA for the management of AIH for the first time, but also provides a novel perspective and a promising therapeutic candidate for the future treatment of autoimmune disorders. Overall design: Mice were randomized into three groups: (1) Normal control, (2) ConA, (3) MSA + ConA. The normal control group received an equivalent volume of sterile phosphate-buffered saline (PBS) via tail vein injection. ConA and MSA were dissolved in sterile PBS to achieve the specified concentrations. The ConA group received a single dose of ConA (20 mg/kg body weight, 4 mg/ml in PBS, Sigma-Aldrich, China) via tail vein injection. The MSA + ConA group received an intraperitoneal injection of MSA (250 mg/kg body weight, 50 mg/ml in PBS, Sigma-Aldrich, China) 6 hours before ConA injection. Twelve hours post-ConA administration, mice were euthanized, and liver tissues (n=3) for RNA-Seq.