Unraveling the role and mechanism of ferroptotic cell death in embryonically derived homeostatic Kupffer cells during NASH development

我们假设新发现的程序性细胞死亡机制铁凋亡是NASH发展过程中库普弗细胞损失的中心调节因子，并且其抑制可以改善NASH进展。枯否细胞是肝脏炎症的关键调节因子，它们维持体内平衡。NASH发展诱导枯否细胞损失和单核细胞衍生的巨噬细胞的募集，这使炎症和纤维化持续存在。铁凋亡是一种由铁依赖性脂质过氧化诱导的细胞死亡机制。毒性脂质物质的积累是NASH的标志，并且在受影响的肝脏中通常发现活性氧（ROS）水平升高。枯否细胞是吞噬细胞，清除大量的脂质负载垂死的肝细胞，并可以积累高铁负荷，由于其在铁代谢中的噬血细胞作用。重要的是，体外研究结果表明，与替代活化的巨噬细胞相比，炎性巨噬细胞的铁凋亡敏感性降低。基于这些观察结果，我们假设铁凋亡是NASH中库普弗细胞丢失的主要机制，减缓调节性库普弗细胞的丢失可能会改善NASH的进展。因此，为了阐明铁凋亡的作用，其对NASH发展中巨噬细胞池的影响以及潜在的代谢途径，我们旨在回答以下三个问题：● 枯否细胞对铁凋亡的敏感性如何，这种敏感性如何随着脂肪变性和NASH的发展而变化？● 库普弗细胞铁凋亡的调节是否可以减缓NASH的进展，以及这种干预如何影响免疫浸润？● NASH微环境中激活了哪些代谢途径，为铁凋亡诱导铺平了道路？

We hypothesize that the newly discovered programmed cell death mechanism ferroptosis is a central regulator of Kupffer cell loss during NASH development and that its inhibition can ameliorate NASH progression. Kupffer cells are key regulators of liver inflammation, and they maintain homeostasis. NASH development induces Kupffer cell loss and recruitment of monocyte-derived macrophages, which perpetuate inflammation and fibrosis. However, the underlying mechanism of Kupffer cell death remains elusive.Ferroptosis is a regulated cell death mechanism induced by iron-dependent lipid peroxidation. Accumulation of toxic lipid species is a hallmark of NASH, and elevated reactive oxygen species (ROS) levels are commonly found in affected livers. Kupffer cells are phagocytes scavenging large amounts of lipid-laden dying hepatocytes and can accumulate high iron loads due to their hemophagocytic role in iron metabolism. Importantly, in-vitro findings suggest a decreased ferroptosis sensitivity of inflammatory macrophages compared to alternatively activated macrophages. Based on these observations, we hypothesize that ferroptosis is a central mechanism responsible for the Kupffer cell loss present in NASH and that decelerating the loss of regulatory Kupffer cells might ameliorate NASH progression.Thus, to unravel the role of ferroptosis, its influence on the macrophage pool in NASH development, and the underlying metabolic pathways, we aim to answer the following three questions:● How susceptible are Kupffer cells to ferroptosis, and how does this susceptibility change with increasing steatosis and NASH development?● Can modulation of Kupffer cell ferroptosis attenuate the progression of NASH, and how does this intervention impact the immune infiltrate?● What metabolic pathways are activated in the NASH microenvironment that pave the way for ferroptosis induction?