HBO-PC Reprograms Neuroimmune Metabolism Through Disruption of the LRG1-HIF-1α-IL-6-STAT3 Amplification Loop Attenuates Pyroptosis and Ischemia-Reperfusion Injury.

BACKGROUND

Neuroinflammation and pyroptosis driven by excessive microglial activation play key roles in cerebral ischemia-reperfusion injury (CIRI). Hyperbaric oxygen preconditioning (HBO-PC) exhibits neuroprotective effects, but its mechanisms remain unclear. Leucine-rich α-2-glycoprotein 1 (LRG1) is implicated in CIRI pathology, yet whether HBO-PC modulates neuroinflammation and pyroptosis via LRG1 is unknown.

METHODS

A mouse CIRI model was generated by middle cerebral artery occlusion. HBO-PC and LRG1 siRNA knockdown were applied. Neurological function and molecular changes were evaluated.

RESULTS

HBO-PC reduced infarct volume and improved neurological outcomes, while downregulating LRG1 in neurons and microglia. LRG1 promoted HIF-1α accumulation by inhibiting prolyl hydroxylase activity, leading to caspase-3-dependent GSDME cleavage and pyroptosis. Released IL-6 activated STAT3, which further transcriptionally upregulated LRG1, forming a self-amplifying HIF-1α/GSDME/IL-6/STAT3 loop. HBO-PC disrupted this circuit and shifted microglia toward an anti-inflammatory phenotype.

CONCLUSION

HBO-PC protects against CIRI by breaking the LRG1-HIF-1α-IL-6-STAT3 feedback loop, thereby attenuating pyroptosis and neuroinflammation while promoting anti-inflammatory microglial polarization. LRG1 represents a promising therapeutic target in ischemic brain injury.