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.

代谢功能障碍相关性脂肪性肝炎（Metabolic dysfunction-associated steatohepatitis, MASH）以脂质蓄积与炎性损伤为核心病理特征。库普弗细胞（Kupffer cells, KC）在肝脏免疫应答及维持代谢稳态的过程中扮演关键角色。本研究旨在探究血红素氧合酶-1（heme oxygenase-1, HO-1）诱导对高碳水化合物饮食诱导的MASH大鼠模型中库普弗细胞活性、肝细胞线粒体稳态及代谢重塑的影响。库普弗细胞内的HO-1诱导可显著减轻肝损伤，具体体现为更低的NAS评分与下调的细胞凋亡相关指标。血红素处理能够恢复氧化平衡并抑制未折叠蛋白反应（Unfolded Protein Response, UPR）的激活。同时，其可修复自噬流与线粒体生物发生过程，增强脂肪酸氧化能力，并改善机体胰岛素敏感性。综上，在MASH大鼠模型中，HO-1诱导可通过减轻氧化应激、缓解内质网应激、促进线粒体周转与代谢适配发挥保肝功效。上述保护效应与库普弗细胞表型向低促炎状态的转变密切相关，这一发现凸显了靶向库普弗细胞的HO-1诱导作为MASH治疗策略的潜在应用价值。