Western Blots used in this study

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by lipid accumulation and inflammatory injury. Kupffer cells (KC) play a key role in the immune response and in achieving metabolic homeostasis in the liver. This study aimed to evaluate the impact of heme oxygenase-1 (HO-1) induction on KC activity, on hepatocyte mitochondrial homeostasis, and on its metabolic switch in a high-carbohydrate diet-induced rat model of MASH. HO-1 induction in KCs significantly reduced liver injury, as evidenced by lower NAS scores and reduced apoptosis parameters. Hemin treatment restored oxidative balance and attenuated UPR activation. It also reinstated autophagic flux and mitochondrial biogenesis, enhanced fatty acid oxidation, and improved insulin sensitivity. In conclusion, HO-1 induction exerts a hepatoprotective role in a rat model of MASH by reducing oxidative stress, alleviating ER stress, and promoting mitochondrial turnover and metabolic adaptations. These effects were associated with a shift in KCs phenotype toward a less pro-inflammatory state, highlighting the potential of KCs-targeted HO-1 induction as a therapeutic approach for MASH.