Metformin protects neurons after brain injury by restoring mitochondrial health

TBI remains a major cause of death and long-term neurological disability worldwide, yet effective treatments for secondary injury are still lacking. Much of the delayed damage arises not only from the initial trauma, but also from persistent oxidative stress, mitochondrial dysfunction, and excessive inflammatory signaling. Among these processes, the NLRP3 inflammasome has emerged as an important driver of neuronal injury because it can trigger pyroptosis, a highly inflammatory form of programmed cell death. At the same time, metformin has shown anti-inflammatory and neuroprotective potential in several neurological disorders. Based on these challenges, in-depth research is needed on how mitochondrial dysfunction and inflammasome activation interact after TBI.

Researchers from Xuanwu Hospital of Capital Medical University, Tianjin Medical University General Hospital, and the People's Hospital of Honghuagang District of Zunyi reported (DOI: 10.1093/burnst/tkag011) in Burns & Trauma on January 28, 2026, that metformin protected neurons after TBI by restoring Mfn1-dependent mitochondrial dynamics, suppressing NLRP3 inflammasome activation, and reducing pyroptotic cell death.

The team first showed that TBI sharply increased the expression of NLRP3, caspase-1, ASC, IL-1β, IL-18, and GSDMD in the injured brain, along with elevated expression of NLRP3, ASC and GSDMD in the neuronal cells, revealing strong inflammasome activation and pyroptosis in neurons. At the same time, the injury disrupted mitochondrial balance: Mfn1, a key fusion protein, was reduced, while phosphorylated Drp1, which promotes fission, increased. These changes were accompanied by mitochondrial fragmentation, loss of membrane potential, and elevated mitochondrial reactive oxygen species. Metformin treatment largely reversed these changes, as evidenced by restored mitochondrial homeostasis, reduced inflammasome-related proteins, and lowered neuronal pyroptosis in both in vivo and in vitro models. The protective effects were also reflected in behavior, with treated mice showing improved neurological scores, better motor coordination, stronger spatial memory, and reduced anxiety-like and depressive-like behavior. Mechanistic experiments added further depth. When Mfn1 was silenced, metformin largely lost its ability to preserve mitochondrial function and suppress inflammasome activation, showing that Mfn1 is essential to this protective effect. The researchers further found that AMPK signaling, rather than mTOR inhibition, was responsible for metformin-driven Mfn1 regulation.

According to the authors, the study highlights Mfn1 as a crucial molecular link between mitochondrial homeostasis and NLRP3 inflammasome. Rather than simply reducing inflammation at the end of the damage pathway, metformin appears to act further upstream by preserving mitochondrial integrity and preventing the danger signals that trigger inflammasome activation. This observation adds significance to the findings, as it points to a more fundamental approach to protecting vulnerable neurons following brain trauma.

The implications of the study extend beyond one repurposed drug. Because metformin is already widely used and well characterized, it may offer a more practical route toward clinical translation than an entirely new therapy. More broadly, the findings place mitochondrial dynamics at the center of future TBI research. If validated in further preclinical and clinical studies, targeting the AMPK-Mfn1 pathway could help reduce secondary brain damage, preserve neuronal survival, and improve long-term recovery after TBI.