2. Academic Validation
  3. HIF-independent oxygen sensing via KDM6A regulates ferroptosis

HIF-independent oxygen sensing via KDM6A regulates ferroptosis

  • Mol Cell. 2025 Aug 7;85(15):2973-2987.e6. doi: 10.1016/j.molcel.2025.07.001.
Alexander M Minikes 1,  Pei Liu 1,  Hua Wang 2,  Jiachen Hu 1,  Hanan Alwaseem 3,  Yueming Li 4,  Xuejun Jiang 5
Affiliations

Affiliations

  • 1 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Peking University International Cancer Institute, Peking University Cancer Hospital and Institute, State Key Laboratory of Molecular Oncology, Peking University Health Science Center, Beijing 100191, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 3 Metabolomics Platform, Rockefeller University, New York, NY 10065, USA.
  • 4 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: jiangx@mskcc.org.
PMID: 40712585 DOI: 10.1016/j.molcel.2025.07.001
Abstract

Ferroptosis, a metabolic cell death process driven by iron-dependent phospholipid peroxidation, is implicated in various pathologies, including Cancer. While metabolic factors such as glucose, lipids, and multiple Amino acids have all been demonstrated to modulate Ferroptosis, the role of oxygen, another fundamental metabolic component, in Ferroptosis is not fully understood. Here, we show that cells acclimated to a low oxygen environment develop marked resistance to Ferroptosis, and this resistance is independent of canonical oxygen-sensing pathway mediated by prolyl hydroxylases (PHDs) and HIF transcription factors. Instead, hypoxia suppresses Ferroptosis by inhibiting KDM6A, a tumor suppressor and oxygen-dependent Histone Demethylase, leading to reduced expression of its transcriptional targets, including lipid metabolic Enzymes ACSL4 and ETNK1, thus rewiring cellular phospholipid profile to a ferroptosis-resistant state. Relevant to Cancer, pharmacological inhibition of the oncogenic Histone Methyltransferase EZH2, which opposes KDM6A activity, restored Ferroptosis sensitivity of xenograft bladder tumor tissues harboring KDM6A mutation.

Keywords

ACSL4; ETNK1; KDM6A; KMT2D; bladder cancer; cancer therapy; ferroptosis; hypoxia; lipid metabolism; oxygen sensing.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z