The increasing prevalence of the spectrum of Steatotic Liver Disease (SLD), including Metabolic-Associated Steatotic Liver Disease (MASLD), Metabolic-Associated Steatohepatitis (MASH), and progression to Cirrhosis and Hepatocellular Carcinoma (HCC) has led to intense research in disease pathophysiology, with many studies focusing on the role of iron. Iron overload, which is often observed in patients with SLD as a part of metabolic hyperferritinaemia (MHF), particularly in the reticuloendothelial system (RES), can exacerbate steatosis. This imbalance in iron distribution, coupled with a high-fat diet, can further promote the progression of SLD by means of oxidative stress triggering inflammation and activating hepatic stellate cells (HSCs), therefore leading to fibrosis and progression of simple steatosis to the more severe MASH. The influence of iron overload in disease progression has also been shown by the complex role of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. Ferroptosis depletes the liver’s antioxidant capacity, further contributing to the development of MASH, while its role in MASH-related HCC is potentially linked to alternations in the tumour microenvironment, as well as ferroptosis resistance. The iron-rich steatotic hepatic environment becomes prone to hepatocarcinogenesis by activation of several pro-carcinogenic mechanisms including epithelial-to-mesenchymal transition and deactivation of DNA damage repair. Biochemical markers of iron overload and deranged metabolism have been linked to all stages of SLD and its associated HCC in multiple patient cohorts of diverse genetic backgrounds, enhancing our daily clinical understanding of this interaction. Further understanding could lead to enhanced therapies for SLD management and prevention.
脂肪性肝病（SLD）谱系，包括代谢相关脂肪性肝病（MASLD）、代谢相关脂肪性肝炎（MASH）及其向肝硬化和肝细胞癌（HCC）的进展，其患病率日益增高，这推动了对该疾病病理生理学的深入研究，其中许多研究聚焦于铁的作用。铁过载常作为代谢性高铁蛋白血症（MHF）的一部分在SLD患者中被观察到，尤其是在网状内皮系统（RES）中，它可能加剧脂肪变性。这种铁分布失衡，加之高脂饮食，可通过氧化应激触发炎症并激活肝星状细胞（HSCs），从而进一步促进SLD的进展，导致纤维化以及单纯性脂肪变性向更严重的MASH发展。铁过载在疾病进展中的影响也通过铁死亡这一复杂作用得到证实，铁死亡是一种由铁依赖性脂质过氧化驱动的细胞死亡方式。铁死亡耗竭肝脏的抗氧化能力，进一步促进MASH的发生，而其在MASH相关HCC中的作用可能与肿瘤微环境的改变以及铁死亡抵抗有关。富含铁的脂肪变性肝脏环境通过激活包括上皮-间质转化和DNA损伤修复失活在内的多种促癌机制，易于发生肝癌。在不同遗传背景的多个患者队列中，铁过载和代谢紊乱的生物化学标志物与SLD的所有阶段及其相关的HCC均有关联，这加深了我们对这种相互作用的日常临床理解。进一步的认知可能有助于开发更有效的SLD治疗和预防策略。
肿瘤(癌症)患者之家