USP11 Drives Cerebral Ischemia–Reperfusion Injury Via Promoting Ferroptosis by Deubiquitinating and Stabilizing ASK1

Background Cerebral ischemia–reperfusion injury (CIRI) represents a pivotal pathological mechanism underlying ischemic cerebrovascular disorders including cerebral stroke. Currently, there are lack of effective preventive or therapeutic methods. Ubiquitin‐specific protease 11 (USP11) is a member of the most prevalent ubiquitination‐specific protease (USP) family. It has been shown that USP11 plays diverse and significant roles in a variety of diseases, such as hepatocellular carcinoma, prostate cancer, and intervertebral disc degeneration. However, its precise function and molecular mechanisms involvement in CIRI remain unknown. Methods USP11 knockout (USP11‐KO) and adeno‐associated virus 9‐mediated USP11 over‐expression (USP11‐OE) mice were established as a mouse model of CIRI, and USP11 knockdown and overexpression adenovirus were used to establish a cell model, to investigate the effect of USP11 on CIRI in vivo and in vitro. Molecular biological studies were used to clarify the mechanism of USP11 mediated ferroptosis during CIRI. Results The expression of USP11 is increased during CIRI. Functionally, USP11 deficiency attenuated neurological deficits, cerebral infarction, neuroinflammation, and ferroptosis during CIRI, whereas specific overexpression of USP11 exacerbated these pathological processes. Furthermore, USP11 knockdown inhibited neuronal injury, inflammatory response and ferroptosis, while USP11 overexpression promoted these processes. Mechanistically, USP11 bind to ASK1 and inhibit its K48‐linked ubiquitination, thereby enhancing the activity of the ASK1‐JNK/p38 signaling pathway. More importantly, the regulation of USP11 on neuronal ferroptosis and CIRI relied on its regulation of the ASK1‐JNK/p38 signaling axis. Conclusions Our study clarified the new functions and mechanisms of USP11 during CIRI. Targeting USP11‐ASK1‐JNK/p38‐ferroptosis may be a new promising strategy for the prevention and treatment of CIRI.