HIF-independent oxygen sensing via KDM6A regulates ferroptosis.

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

SUBMITTER: Minikes AM 

PROVIDER: S-EPMC12313182 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature