Dietary sulforaphane modulates hepatic anti-oxidative genes via REV-ERBα and histone modifications in pigs

Sulforaphane (SFN) is a naturally occurring isothiocyanate found in cruciferous vegetables known for its anti-inflammatory and antioxidant effects in the body. However, whether its dietary addition impacts porcine liver health remains unclear, and if it does, the mechanisms are unknown. In this study, supplementing the diet of growing pigs with 1 g kg^–1 SFN was found to improve growth performance and hepatocellular proliferation. Further analyses revealed that SFN reduced hepatic and serum malondialdehyde levels, while increasing glutathione peroxidase (GSH-PX) activity in the liver. Transcriptomic and proteomic studies demonstrated that SFN down-regulated multiple pathways, including oxidative phosphorylation, inflammatory responses, IL-6-JAK-STAT3 signaling, and TNFα signaling via NFκB. Meanwhile, it upregulated NRF2/GPX4/HO-1 expression and reduced IL-6 and TNFα expression. Mechanistic studies identified potential NR1D1 and NRF2 binding elements in the promoters of the GPX4 and HO-1 genes in the liver. Furthermore, metabolomic profiling revealed a decline in serum β-hydroxybutyrate levels after the administration of SFN, while further analysis confirmed that SFN enhanced a type of epigenetic modification in the liver, lysine β-hydroxybutyrylation (Kbhb). These results highlight the protective roles of SFN against liver inflammation and oxidative damage, and a novel mechanism involving NRF2 and NR1D1 synergy is proposed, although the promotion of hepatic Kbhb by SFN still requires further exploration.