Sulforaphane regulation autophagy-mediated pyroptosis in autoimmune hepatitis via AMPK/mTOR pathway

Autoimmune hepatitis (AIH) is a liver disease marked by inflammation of unknown origin. If untreated, it can progress to cirrhosis or liver failure, posing a significant health risk. Currently, effective drug therapies are lacking in clinical practice. Sulforaphane (SFN), a natural anti-inflammatory and antioxidant compound found in various cruciferous vegetables, alleviate pyroptosis and improve impaired autophagic flux, both of which contribute to AIH progression. However, whether SFN modulates autophagic flux and pyroptosis in S100-induced EAH through the AMPK/mTOR pathway remains unclear. Therefore, this study aims to investigate whether SFN can regulate AIH and elucidate its potential mechanisms of action. In this study, experimental AIH (EAH) was induced in male C57BL/6 J mice through intraperitoneal (i.p.) injection of S100. SFN was administered intraperitoneally every other day. After 28 days, the mice were euthanized, and their livers and serum were collected for histological and biochemical analyses. AML12 cells were used for the in vitro studies. The results showed that SFN mitigated pyroptosis by inhibiting the NLRP3 inflammasome and improving autophagic flux, which alleviates S100-induced EAH. Conversely, the autophagy inhibitor 3-MA negated the protective effects of SFN against inflammasome-mediated pyroptosis. Furthermore, SFN activated the AMPK/mTOR signaling pathway, offering protection against S100-induced EAH. Selective inhibition of AMPK suppressed the improvement in autophagic flux and protected against SFN-induced pyroptosis. Overall, SFN significantly ameliorates S100-induced EAH by enhancing autophagic flux and mitigating pyroptosis through activation of the AMPK/mTOR signaling pathway.