Saif Dhahir, Fatma M Amin, Manar A Nader
Background: Autoimmune hepatitis (AIH) represents a clinically challenging immune-mediated liver disease, owing to its complex pathogenesis and limited targeted therapeutic options. Growing evidence highlights the key role of lymphocyte-mediated hepatic inflammation, dysregulated cytokine milieu, and oxidative stress in AIH progression. Oridonin (ORI), a bioactive diterpenoid with well-established antioxidant, anti-inflammatory, and immunoregulatory effects, remains unexplored in AIH. The present work aims to survey the potential impacts of ORI in Concanavalin A (Con A)-prompted AIH in mice, with particular emphasis on TLR7/PKM2/NLRP3 inflammatory signaling and macrophage polarization. Methods: Male BALB/c mice (n = 30) were allocated into five groups: CTR group, ORI-CTR group, Con A group, ORI (5 mg/kg) + Con A group, and ORI (10 mg/kg) + Con A group. ORI was administered i.p. for 4 days before a single Con A injection (15 mg/kg i.v.). Serum liver enzymes, hepatic pathological changes, oxidative milieu, and varied immunological factors were assessed. Results: ORI markedly attenuated Con A-induced hepatic injury, as evidenced by the reduced liver transaminases, preserved hepatic architecture, and restored oxidative milieu. Moreover, ORI suppressed T-cell activation, modulated M1/M2 polarization, and reduced pro-inflammatory cytokines. These effects were accompanied by the suppression of TLR7/PKM2/NLRP3 inflammatory signaling. Conclusions: ORI exhibits hepatoprotective effects against Con A-induced AIH and these effects are associated with the modulation of inflammatory and immunometabolic responses as well as downregulating TLR7/PKM2/NLRP3 signaling.