PKM2 accelerated the progression of chronic fatigue syndrome via promoting the H4K12la/ NF-κB induced neuroinflammation and mitochondrial damage. — CFSMEATLAS
PKM2 accelerated the progression of chronic fatigue syndrome via promoting the H4K12la/ NF-κB induced neuroinflammation and mitochondrial damage.
Sun, Meng, Zhang, Xinwen, Feng, Xinli et al. · Scientific reports · 2025 · DOI
Quick Summary
This study in mice explored how a protein called PKM2 may contribute to ME/CFS by increasing inflammation in the brain and damaging energy-producing structures inside cells (mitochondria). Researchers found that when PKM2 levels increased, cognitive problems worsened and brain cells showed more damage, while reducing PKM2 improved these outcomes. The mechanism involves lactate buildup and activation of inflammatory pathways in the brain.
Why It Matters
Understanding the molecular pathways driving ME/CFS is critical for developing targeted treatments. If PKM2-mediated neuroinflammation and mitochondrial damage are confirmed in human patients, inhibiting PKM2 or its downstream signaling could represent a novel therapeutic strategy for cognitive and physical dysfunction in ME/CFS.
Observed Findings
PKM2 overexpression worsened cognitive function in the mouse model, while PKM2 knockdown improved it compared to untreated CFS-like mice.
Brain tissue lactate levels increased in CFS-like mice and further elevated with PKM2 overexpression; PKM2 knockdown reduced these levels.
Markers of inflammation (IL-1β, TNFα) and histone lactylation (H4K12la) were elevated in CFS-like mice and further increased with PKM2 overexpression.
Hippocampal CA1 neurons showed disorganization and reduced cell quantity in CFS-like mice; PKM2 overexpression worsened this, while PKM2 knockdown improved cell organization.
Physical strength (grip strength, rotation tests) showed no significant differences across treatment groups in the tested parameters.
Inferred Conclusions
PKM2 enhances glycolysis and lactate accumulation in hippocampal cells, promoting H4K12 histone lactylation.
H4K12 lactylation drives NF-κB-mediated neuroinflammation, leading to neuronal damage and cognitive decline.
PKM2 modulation may be a potential therapeutic target for CFS-related neuroinflammation and cognitive dysfunction.
Mitochondrial damage in the brain may be a key mechanism linking PKM2 activity to CFS progression.
Remaining Questions
What This Study Does Not Prove
This study does not prove that PKM2 dysfunction causes ME/CFS in humans, as it was conducted only in a mouse model with an artificially induced CFS-like state. The findings suggest a potential mechanism but do not establish that human ME/CFS patients have elevated PKM2 activity or that modulating PKM2 would be safe or effective as a treatment. Correlation between PKM2 levels and CFS severity in patients remains undemonstrated.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →