Isoliquiritigenin ameliorates metabolic dysfunction-associated steatotic liver disease by modulating S100A8-associated MAPK signaling and ferroptosis-related processes

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) currently lacks effective targeted therapeutic approaches. Although isoliquiritigenin (ISL) exhibits hepatoprotective effects, its precise molecular target remains unclear. This study aims to identify the potential molecular target and mechanism of ISL in MASLD. Methods: HFD-induced MASLD mice were treated with ISL, while palmitic acid (PA)-challenged HepG2 cells were used as an in vitro lipotoxicity model. RNA sequencing (RNA-seq), molecular docking, cellular thermal shift assay (CETSA), and S100A8 overexpression plasmids were employed to investigate the underlying molecular mechanism. Results: In vivo , ISL significantly reduced serum transaminases, hepatic lipid accumulation, and fibrosis. RNA-seq showed that ISL mainly regulated ferroptosis and the mitogen-activated protein kinase (MAPK) pathway, with S100A8 identified as an important candidate regulatory target. Molecular docking and CETSA assays point toward a possible direct interaction between ISL and S100A8, implying that ISL could improve the thermal stability of S100A8. In vitro , ISL reversed PA-triggered lipid accumulation, reduced lipid peroxidation as indicated by MDA levels, restored glutathione peroxidase 4 (GPX4) expression, inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, and suppressed phosphorylation of p38 and p44/42 MAPK. ISL interacted with S100A8 and modulated S100A8-associated MAPK signaling and ferroptosis, thereby alleviating lipotoxic liver injury and fibrosis. Conclusion: These findings support S100A8 as an important mediator of ISL's protective effects and provide a mechanistic basis for its potential application in MASLD