生酮-铁死亡轴维持白血病干细胞存活和白血病进展
生酮-铁死亡轴维持白血病干细胞存活和白血病进展
作者： 小柯机器人 发布时间：2026/5/12 18:14:35
本期文章：《细胞—干细胞》：Online/在线发表
中山大学蒋琳加小组取得一项新突破。他们研制了生酮-铁死亡轴维持白血病干细胞存活和白血病进展。该项研究成果发表在2026年5月11日出版的《细胞—干细胞》上。
研究小组发现急性髓性白血病（AML）中的白血病干细胞（LSCs）在脂肪酸氧化（FAO）的驱动下表现出升高的酮生成，以产生β-羟基丁酸（BHB）。与母细胞和正常造血干细胞（hsc）相比，LSCs表达高水平的3-羟基-3-甲基戊二酰辅酶A （CoA）合成酶2 (HMGCS2)，这是生酮过程中的限速酶。AML细胞中Hmgcs2的缺失显著降低BHB水平，破坏LSC功能，并在小鼠和人类AML模型中损害白血病进展，同时在很大程度上保留正常的造血功能。从机制上说，BHB通过表观遗传调控脂肪酸去饱和酶2 （FADS2）来限制亲铁沉磷脂重塑，从而抑制铁死亡。综上所述，这些发现确定自主细胞生酮是一个关键的代谢程序，可以保护LSCs免于嗜铁性细胞死亡，并阻止白血病的进展。
据介绍，在碳水化合物限制或生酮饮食期间，肝生酮产生酮体作为替代能量来源，但其在非肝细胞类型中的作用仍不明确。
附：英文原文
Title: A ketogenesis-ferroptosis axis maintains leukemic stem cell survival and leukemia progression
Author: Xue Han, Kexin Wang, Weiwei Ma, Songqi Zhu, Jingjing Guan, Xiaobin Tian, Zhuangzhuang Zhao, Linjia Jiang
Issue&Volume: 2026-05-11
Abstract: Hepatic ketogenesis generates ketone bodies as an alternative energy source during carbohydrate restriction or ketogenic diets, yet its role in non-hepatic cell types remains poorly defined. Here, we show that leukemic stem cells (LSCs) in acute myeloid leukemia (AML) exhibit elevated ketogenesis, driven by fatty acid oxidation (FAO), to produce β-hydroxybutyrate (BHB). LSCs express high levels of 3-hydroxy-3-methylglutaryl-coenzyme A (CoA) synthase 2 (HMGCS2), the rate-limiting enzyme in ketogenesis, compared with blast cells and normal hematopoietic stem cells (HSCs). Deletion of Hmgcs2 in AML cells markedly decreases BHB levels, disrupts LSC function, and impairs leukemia progression in both mouse and human AML models while largely sparing normal hematopoiesis. Mechanistically, BHB suppresses ferroptosis by limiting pro-ferroptotic phospholipid remodeling through epigenetic regulation of fatty acid desaturase 2 (FADS2). Together, these findings identify autonomous ketogenesis as a critical metabolic program that protects LSCs from ferroptotic cell death and sustains leukemia progression.
DOI: 10.1016/j.stem.2026.04.013
Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(26)00153-0