血清载脂蛋白 H 通过调节细胞脂质组成决定了铁死亡抗性。

Serum apolipoprotein H determines ferroptosis resistance by modulating cellular lipid composition.

机构信息

Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

出版信息

Cell Death Dis. 2024 Oct 1;15(10):718. doi: 10.1038/s41419-024-07099-2.

DOI:10.1038/s41419-024-07099-2

PMID:39353906

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11445452/

Abstract

Ferroptosis is a regulated cell death process dependent on iron, triggered by the accumulation of lipid peroxidation. The environmental context significantly impacts cellular sensitivities to ferroptosis. Serum, constituting the extracellular fluid composition in vivo, provides crucial environmental biomolecules. In this study, we investigated the influence of sera on ferroptosis induction, pinpointing the serum protein apolipoprotein H (APOH) as a pivotal inhibitor of ferroptosis. Moreover, we elucidated that APOH suppresses ferroptosis by activating the phosphoinositide 3-kinase (PI3K)-AKT-sterol regulatory element-binding proteins (SREBPs) pathway, thereby elevating stearoyl-CoA desaturase (SCD) levels and augmenting cellular monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Furthermore, ApoHinfer, the peptide derivative of the active region of APOH, mimics its ferroptosis inhibitory activity. Our findings underscore the critical role of serum protein APOH in the inhibition of ferroptosis and indicates potential therapeutic applications in treating cancer and diseases associated with ferroptosis.

摘要

铁死亡是一种依赖于铁的受调控的细胞死亡过程，由脂质过氧化积累引发。环境背景显著影响细胞对铁死亡的敏感性。血清构成了体内细胞外液的组成，提供了关键的环境生物分子。在这项研究中，我们研究了血清对铁死亡诱导的影响，确定了血清蛋白载脂蛋白 H（APOH）是铁死亡的关键抑制剂。此外，我们阐明了 APOH 通过激活磷脂酰肌醇 3-激酶（PI3K）-AKT-固醇调节元件结合蛋白（SREBPs）通路抑制铁死亡，从而提高硬脂酰辅酶 A 去饱和酶（SCD）水平并增加细胞中单不饱和脂肪酸含量的磷脂（MUFA-PLs）。此外，APOHinfer 是 APOH 活性区域的肽衍生物，模拟了其铁死亡抑制活性。我们的研究结果强调了血清蛋白 APOH 在抑制铁死亡中的关键作用，并表明其在治疗癌症和与铁死亡相关疾病方面具有潜在的治疗应用。