Mitochondrial dysfunction, neuroinflammation, and associated mechanisms in sepsis-associated encephalopathy: from pathogenesis to emerging therapeutics.

Sepsis-associated encephalopathy (SAE) is a devastating neurological complication of sepsis, leading to diffuse brain dysfunction, long-term cognitive deficits, and increased mortality. Its pathogenesis is complex, with mitochondrial dysfunction and neuroinflammation emerging as central, interconnected drivers. This review systematically elucidates the pathogenic crosstalk between these two processes. We detail how dysregulated mitochondrial dynamics (e.g., Drp1-mediated fission), impaired biogenesis (via the proliferator-activated receptor-gamma coactivator-1α axis), oxidative stress, and the activation of mitochondria-dependent cell death pathways (ferroptosis, pyroptosis) contribute to neuronal injury. Concurrently, microglial activation, particularly through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, creates a vicious cycle that exacerbates mitochondrial damage and synaptic loss. Furthermore, we summarize emerging therapeutic strategies that target this mitochondrial-neuroinflammatory axis, including molecular hydrogen, mitochondria-targeted peptides (), natural compounds, and specific inhibitors (e.g.,,). The integration of recent insights on the gut-brain axis and cerebral metabolomics further expands the therapeutic landscape. Ultimately, targeting this core axis offers a promising paradigm for developing effective interventions to improve neurological outcomes in septic patients.