Hydroxytyrosol Prevents Metabolic-Associated Steatohepatitis by Inhibiting SOCS2-Mediated Ferroptosis in High-Fat Diet Mice

Metabolic dysfunction associated with fatty liver disease (MAFLD) affects 30% of the global population, and preventing its progression to metabolic dysfunction-associated steatohepatitis (MASH) is crucial. In this study, we explored the role of hydroxytyrosol (HT), an active polyphenol in extra virgin olive oil with antioxidant and metabolic regulatory effects, in preventing MASH via suppressors of cytokine signaling 2 (SOCS2)-mediated ferroptosis. In vivo, high-fat-diet (HFD)-fed mice (16 weeks) developed MASH with hepatic ferroptosis, which was alleviated by HT gavage. In vitro, palmitic acid (PA)-induced hepatocyte ferroptosis and stellate cell fibrosis were reversed by HT or SOCS2 knockdown but abolished by SOCS2 overexpression. Combined with the coimmunoprecipitation assay, we further elucidated that HT reduced the binding of SOCS2 to SLC7A11, decreased the ubiquitination and degradation of SLC7A11, thereby restoring GPX4 protein levels. Thus, HT delays MASH progression by targeting the SOCS2/SLC7A11/GPX4 axis to inhibit ferroptosis, providing a novel clinical intervention strategy.