Traumatic brain injury (TBI) is a devastating neurological condition characterized by extremely high rates of death and long-term disability, with effective therapeutic interventions remaining severely limited. Following a TBI, a major driver of irreversible brain damage is necroptosis, a highly regulated form of inflammatory cell death involving the rupture of the plasma membrane. While the mammalian target of rapamycin (mTOR) signaling network is known to influence various forms of cell death, the specific mechanisms governing necroptosis—particularly the potential role of the key mTORC1 substrate S6K1—have remained largely elusive.

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

Funding Information:
The National Natural Science Foundation of China (No. 82101126, No. 82572869, No. 82172196, No. 82372507, No. 81371011, No. 81671225)
The Natural Science Foundation of Hunan Province, China (No. 2024JJ5472, No. 2021JJ40873)
The Scientific Research Launch Project for new employees of the Second Xiangya Hospital of Central South University (China)
The Flexible Talent Introduction Program of Central South University (China)

# # # # # #

Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 10.4 | Impact Factor: 14.6

# # # # # #

More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Diseases may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.cn
X (formerly twitter): @GenesNDiseases (https://x.com/GenesNDiseases)

# # # # # #