Sepsis: Epidemiology, Pathophysiology, and Management

ABSTRACT Sepsis remains a major cause of global morbidity and mortality despite advances in recognition, antimicrobial therapy, and organ support, reflecting its biological heterogeneity and the absence of broadly effective host‐directed treatments. Here, we synthesize recent evidence across the three domains that define contemporary sepsis: epidemiology, pathophysiology, and management. Global and regional data indicate a persistently high but uneven burden, shaped by differences in case definitions, population structure, healthcare resources, and ascertainment. Mechanistically, sepsis is best viewed as an interconnected systems disorder in which hyperinflammation and immunoparalysis coexist with oxidative stress, endothelial and coagulation injury, immunometabolic dysfunction, gut dysbiosis, mitochondrial damage, and dysregulated programmed cell death, collectively driving organ dysfunction. Current management remains centered on timely antimicrobials, source control, individualized fluid and vasopressor therapy, corticosteroids, and organ support, while biomarker‐guided immunotherapy and other host‐directed strategies remain investigational. Recent randomized trials have mainly refined how established treatments are delivered rather than identified a universally effective new therapy. We also evaluate preclinical evidence for natural compounds targeting inflammatory and cell‐death networks and highlight persistent methodological, pharmacokinetic, and translational barriers. Integrating rigorous phenotyping, mechanistic biomarkers, and guideline‐based care may provide a more realistic path toward precision sepsis therapy.