Inhibition of PTEN nuclear translocation by peptide Tat-K13 attenuates p-JUN-SESN2-AMPK-dependent autophagy and enhances neurological recovery after neonatal hypoxic-ischemic brain damage.

Neuronal death triggered by hypoxia-ischemia (HI) is a major cause of neonatal mortality and long-term neurological deficits. Excessive autophagy plays a pathogenic role in neonatal hypoxic-ischemic encephalopathy (HIE), and inhibition of phosphatase and tensin homolog deleted on chromosome TEN (PTEN) nuclear translocation has been shown to suppress autophagy. Our recent study demonstrated that blocking PTEN nuclear import with the peptide Tat-K13 mitigates HI-induced behavioral impairments. However, the underlying mechanism remains unclear. Here, we found that HI activated the p-JUN-SESN2-AMPK signaling pathway in both in vivo and in vitro models of neonatal hypoxic-ischemic brain damage (HIBD). Downregulation of JUN reduced neuronal loss and improved behavioral outcomes in HIBD rats. Furthermore, Tat-K13-mediated blockade of PTEN nuclear translocation attenuated HI-induced activation of the p-JUN-SESN2-AMPK pathway and suppressed autophagy. Notably, the neuroprotective and behavioral benefits conferred by Tat-K13 were achieved through autophagy inhibition resulting from suppression of this signaling cascade. These findings identify targeting PTEN nuclear import with Tat-K13 as a potential therapeutic strategy for neonatal HIE, acting via the p-JUN-SESN2-AMPK-autophagy axis to promote neuronal survival and functional recovery.