Cellular Recycling Switch SIRT1-FOXO1 May Hold Key to Taming Brain Inflammation

When the brain’s immune sentinels spiral out of control, the consequences can be devastating, fueling the tissue damage that follows stroke and other neurological insults. Now, a team of neurosurgeons in Shaanxi Province, China, has mapped a molecular braking system that keeps these cells from overheating. In a study published in BMC Neuroscience, Xiaogang Yang, Xin Ai, Hongxing Sun and Wei Shi report that the SIRT1-FOXO1 signaling axis acts as a critical negative regulator of mitophagy and glycolytic metabolism in macrophages exposed to inflammatory triggers. Their findings suggest that this pathway, which coordinates how immune cells recycle damaged mitochondria and rewire their energy production, could represent a promising therapeutic target for neuroinflammatory diseases such as ischemic stroke.

The researchers built their investigation around one of the most widely used models of cellular inflammation. They treated RAW264.7 macrophages, a mouse immune cell line, with lipopolysaccharide, or LPS, a molecule derived from the outer membrane of certain bacteria that reliably provokes a fierce inflammatory response. LPS exposure mimics the molecular alarm bells that ring during infection and tissue injury, and it is a standard tool for probing how immune cells behave when the body’s danger signals are blazing. Within this model, the team set out to dissect what happens when the balance between two key proteins, SIRT1 and FOXO1, is disturbed.

SIRT1 is a deacetylase enzyme, a member of the sirtuin family that has long been associated with cellular longevity, metabolic regulation and stress resistance. It works chemically by removing acetyl groups from target proteins, altering their activity. FOXO1, meanwhile, is a transcription factor, a DNA-binding protein that switches genes on and off. Previous work had hinted that SIRT1 could modify FOXO1 and influence its function, but the downstream consequences for mitochondrial quality control and immune cell metabolism remained incompletely understood. The new study set out to test whether SIRT1 restrains FOXO1 and, in doing so, protects cells from runaway inflammation.

To manipulate the pathway, the researchers used molecular tools to silence SIRT1 or to force cells to overexpress FOXO1. Both interventions produced strikingly similar effects, revealing that SIRT1 normally acts upstream to hold FOXO1 in check. When SIRT1 was knocked down, or when FOXO1 was artificially elevated, the cells dramatically increased production of PINK1 and Parkin, the two central proteins of the mitophagy machinery. Mitophagy is the process by which cells identify damaged mitochondria and tag them for destruction and recycling, and PINK1 and Parkin are the quality-control officers who flag defective organelles for removal. In principle, mitophagy is beneficial, clearing out dysfunctional power plants before they leak harmful reactive molecules. But the study showed that too much of a good thing can be toxic.

With PINK1 and Parkin ramped up excessively, the macrophages suffered a collapse of mitochondrial membrane potential, the electrical gradient across the inner mitochondrial membrane that drives energy production. Using the JC-1 fluorescent probe, the team visualized this dissipation directly, finding that the cells’ cellular power stations were losing their charge. The consequences rippled outward. The cells released elevated amounts of tumor necrosis factor-alpha and interleukin-1 beta, two potent inflammatory cytokines that amplify immune responses and can damage surrounding tissue. Levels of malondialdehyde, a widely used marker of oxidative lipid damage, also climbed, indicating that the cells were under heavy oxidative stress. In short, the SIRT1-FOXO1 imbalance pushed the macrophages into a hyperinflammatory state.

The metabolic rewiring was equally dramatic. The team measured glucose uptake, lactate production and ATP levels, and all three rose when the axis was disrupted. Key glycolysis-related proteins were upregulated, pointing to a shift toward aerobic glycolysis, the glucose-burning mode famously favored by rapidly dividing and highly activated immune cells. This metabolic switch, sometimes called the Warburg-like state, allows activated macrophages to generate building blocks and rapid bursts of energy even when oxygen is plentiful. But it came at a cost: the cellular microenvironment became acidified, as the surplus glucose was converted into lactate and exported from the cells. The combination of cytokine flooding, oxidative damage and acidic surroundings paints a picture of a tissue environment primed for injury.

To confirm that these changes were driven by the autophagy machinery itself, the researchers deployed two pharmacological modulators acting at different points in the autophagy pathway. Rapamycin, an inhibitor of the mTOR pathway and a well-established enhancer of autophagy, further intensified the phenotypes triggered by the SIRT1-FOXO1 imbalance, worsening membrane potential loss and inflammatory output. Conversely, 3-methyladenine, known as 3-MA, which blocks an early step of autophagosome formation, attenuated the same phenotypes. This push-pull experiment provides mechanistic weight to the central claim: the inflammatory and metabolic damage observed when SIRT1 is silenced or FOXO1 is elevated flows substantially through excessive activation of mitophagy and the associated metabolic shift.

The broader significance of the work lies in its implications for the brain. Macrophage-like immune cells, including the brain’s resident microglia and infiltrating macrophages, are central players in neuroinflammation, the chronic or excessive inflammatory response within nervous tissue that accompanies ischemic stroke, traumatic brain injury and neurodegenerative disease. If the SIRT1-FOXO1 axis functions similarly in these cells, then bolstering SIRT1 activity or damping FOXO1 signaling could help keep mitochondrial quality control within healthy bounds, preserving energy metabolism and reducing the release of cytokines that injure vulnerable neurons. The authors propose that this pathway may represent a potential therapeutic target for neuroinflammatory diseases such as ischemic stroke, where limiting secondary inflammatory damage is a major unmet clinical need.

The study, conducted by researchers affiliated with the Second Affiliated Hospital of Xi’an Jiaotong University and the Affiliated Hospital of Yan’an University, was supported by the Yan’an Science and Technology Plan and the Shaanxi Provincial Health and Wellness Research Innovation Platform. As with all cell-line work, important caveats remain. RAW264.7 macrophages are a laboratory model, and the behavior of these engineered cells must be validated in primary cells, in animal models of stroke and eventually in human tissue before any clinical translation can occur. The doses of LPS and the genetic manipulations used in vitro do not perfectly reproduce the complex inflammatory milieu of a diseased brain. Nevertheless, the study offers a clear and testable model: SIRT1 negatively regulates FOXO1, and this restraint prevents excessive mitophagy, preserves mitochondrial membrane potential, restrains the glycolytic shift and keeps inflammatory cytokine release in check. For a field searching for ways to quiet the immune storm that follows brain injury, that model is a compelling roadmap for the next generation of experiments.

Subject of Research: The SIRT1-FOXO1 signaling axis regulates mitophagy and glycolytic metabolism in LPS-stimulated macrophages with implications for neuroinflammation.

Article Title: SIRT1/FOXO1 axis regulates mitophagy and glycolytic metabolism in LPS-stimulated macrophages: implications for neuroinflammation

Article References: Yang, X., Ai, X., Sun, H., & Shi, W. (2026). SIRT1/FOXO1 axis regulates mitophagy and glycolytic metabolism in LPS-stimulated macrophages: implications for neuroinflammation. BMC Neuroscience. https://doi.org/10.1186/s12868-026-01038-x

Image Credits: AI Generated

DOI: 10.1186/s12868-026-01038-x

Keywords: SIRT1, FOXO1, mitophagy, macrophages, glycolysis, neuroinflammation, LPS, inflammatory cytokines, ischemic stroke, mitochondrial membrane potential, PINK1, Parkin