SIRT1 Activation Ameliorates Neuroinflammation and Cognitive Impairment in a Murine SAE Model and is Associated with the Nrf2/GPX4 Pathway.

Sepsis-associated encephalopathy (SAE) is a devastating condition with high mortality and cognitive sequelae, yet no effective treatments. This study investigates the neuroprotective potential of selective Sirtuin 1 (SIRT1) activation using the synthetic agonist SRT1720 in a male C57BL/6 J murine model of SAE. Transcriptomic profiling of the hippocampus revealed a specific disruption in glutathione and arachidonic acid metabolism pathways, indicating a metabolic priming for ferroptosis. We demonstrate that SIRT1 activation improves survival and ameliorates cognitive deficits by concurrently attenuating hippocampal ferroptosis and neuroinflammation. We observed that this protection was associated with the upregulated protein expression of Nrf2 and GPX4, key regulators of ferroptosis. Mechanistically, SIRT1 activation suppressed hippocampal ferroptosis, marked by reduced lipid peroxidation (ROS and MDA). Concurrently, it attenuated neuroinflammation by suppressing microglial activation and NLRP3 inflammasome activity, thereby decreasing the maturation of proinflammatory cytokines. These findings suggest SIRT1 activation coordinately counteracts both ferroptotic and inflammatory damage in SAE, presenting a compelling therapeutic strategy.