Year: 2026
Type: preprint
Abstract: Ferroptosis is driven by lipid peroxidation 1–3 , yet the mechanisms by which cells rapidly adjust their sensitivity to ferroptosis in response to extracellular cues remain elusive. We identify a direct phosphorylation switch controlling the activity of glutathione peroxidase 4 (GPX4), the core ferroptosis regulator 4 . The receptor tyrosine kinase (RTK) FGFR1 directly binds and phosphorylates GPX4 at Tyr180/Tyr196 in a kinase-dependent manner, requiring FGFR1 Tyr730 as a docking site. This phosphorylation enhances GPX4’s catalytic activity and suppresses ferroptosis. In cardiac ischemia/reperfusion injury, the FGFR1-GPX4 axis is suppressed, and a selective FGFR1 agonist (FGF-1 ΔNT ) reactivates it to protect against ferroptosis-mediated damage. Critically, a phosphorylation-deficient GPX4 knock-in mouse exhibits hypersensitivity to injury and is non-responsive to this agonist, demonstrating that GPX4 phosphorylation is essential. Our findings reveal a rapid mechanism for regulating ferroptosis via GPX4 tyrosine phosphorylation, directly linking RTK signaling to ferroptosis, and offering new strategies for treating ischemic-and other ferroptosis-associated diseases.
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7165636258