TRIM32 promotes neuronal ferroptosis by enhancing K63-linked ubiquitination and subsequent p62-selective autophagic degradation of GPX4

Abstract

showed aggravated neuronal loss and poor behavioral function, which could be attenuated by ferroptosis inhibitor Liproxstatin-1. Mechanistically, TRIM32 interacted with GPX4, promoted K63-linked ubiquitination modification of GPX4 at K107, thus enhanced p62-dependent autophagic degradation of GPX4. Moreover, ROS-ATM-Chk2 signaling pathway phosphorylates TRIM32 at S55, further contributing to GPX4 ubiquitination and degradation and subsequent neuronal ferroptosis after SCI, suggesting a positive feedback loop between ROS and TRIM32. Clinically, lipid peroxidation was significantly promoted in patients with SCI. These findings reveal that TRIM32 functions as a neuronal ferroptosis enhancer which is detrimental to neuronal survival and locomotor functional recovery in mice after SCI by promoting K63-linked ubiquitination and subsequent p62-dependent autophagic degradation of GPX4, suggesting a promising therapeutic target for SCI.