Delta-8-Tetrahydrocannabinol Mitigates Murine Autoimmune Hepatitis through Epigenetic Regulation of Immune Dynamics

ABSTRACT: Autoimmune hepatitis (AIH) is an immune-mediated liver disease characterized by an imbalance between effector and regulatory immune responses. Epigenetic regulation, particularly via microRNAs (miRNAs), is emerging as a critical modulator of the immune system during inflammatory diseases. Cannabinoids are increasingly recognized for their immunosuppressive and anti-inflammatory properties; however, the impact of delta-8-tetrahydrocannabinol (Δ⁸-THC), a novel minor compound found in Cannabis plant with less psychoactive property than Δ⁹-THC, remains entirely unexplored in combating autoimmune hepatitis. To address this gap, we investigated the immunoregulatory and hepatoprotective effects of Δ⁸-THC in Concanavalin A (ConA)-induced murine model of AIH. We found that Δ⁸-THC effectively ameliorated ConA-induced liver injury by restoring intrahepatic innate and adaptive immune homeostasis through the preservation of tolerogenic Kupffer cells, suppression of inflammatory monocytes, neutrophils, and natural killer cells. Moreover, Δ⁸-THC reversed the inflammatory lymphoid microenvironment in the liver caused by ConA by decreasing inflammatory CD4+ T cells and promoting expansion of regulatory T cells. These effects were correlated with the preservation of hepatoprotective miR-199a-3p and miR-100-5p expression in hepatic immune cells that were markedly downregulated in ConA-treated mice. Ingenuity Pathway Analysis identified mTOR, a key immune regulator of T cell differentiation, as a target of these miRNAs. Consistently, Δ⁸-THC treatment reduced hepatic mTOR expression in vivo and in vitro. Functional assays using miRNA mimics and inhibitors confirmed direct regulation of mTOR by these miRNAs, where miRNA-mediated mTOR suppression promoted regulatory T cells differentiation and inhibited Th1 and Th17 responses. Together, these findings identify Δ⁸-THC is as a novel anti-inflammatory and hepatoprotective compound that attenuates autoimmune liver injury through epigenetic regulation of the miRNA-mTOR signaling axis, revealing its potential immunomodulatory effects in autoimmune and inflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE319930 | GEO | 2026/02/18

REPOSITORIES: GEO