This new research, published in the Genes & Diseases journal by a collaborative team from Central South University and Kunming Medical University, investigated the non-canonical role of the S6K1 and glucocorticoid-inducible kinase-1 (SGK1) pathway in regulating neuronal necroptosis.
Through rigorous in vitro experiments utilizing a TSZ-induced necroptotic neuronal cell model alongside advanced RNA sequencing, the researchers discovered a profound activation of both S6K1 and SGK1 during the necroptotic process. Extensive molecular assays deciphered the underlying relationship between these kinases, revealing that S6K1 acts as a critical upstream regulator that enhances SGK1 expression, rather than directly binding to it. This elevated SGK1 subsequently drives the robust activation of MLKL, a core executioner protein responsible for finalizing necroptotic cell death. Crucially, the researchers demonstrated that genetically silencing or pharmacologically inhibiting either S6K1 or SGK1 successfully halted MLKL activation and significantly rescued the neurons from necroptosis.
Remarkably, comprehensive in vivo evaluations using a controlled cortical impact mouse model of TBI confirmed the clinical relevance of this newly mapped pathway. The data conclusively showed that administering the S6K1 inhibitor PF4708671 or an AAV-mediated S6K1 knockdown significantly alleviated neuronal necroptosis and considerably suppressed trauma-induced neuroinflammation.
By reducing the widespread activation of microglia and astrocytes, as well as minimizing the massive release of pro-inflammatory cytokines, this targeted S6K1 inhibition dramatically mitigated severe brain tissue edema. Furthermore, extensive behavioral and cognitive testing revealed that silencing this axis rescued motor coordination and alleviated functional deficits in the injured mice.
In conclusion, targeting this non-canonical S6K1-SGK1 pathway offers a powerful new strategy to halt necroptosis and neuroinflammation. This finding directly positions specific S6K1 inhibitors as highly compelling, next-generation therapeutic candidates capable of improving recovery and long-term outcomes for patients suffering from severe traumatic brain injury.
Reference
Title of Original Paper: Non-canonical role of “S6K1–SGK1” pathway in neuronal necroptosis following traumatic brain injury
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101876
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