Vol. 9, Special Issue 12, Part P (2025)

Sepsis is a life-threatening clinical syndrome resulting from a dysregulated host response to infection and remains a major cause of morbidity and mortality worldwide. Despite advances in antimicrobial therapy and critical care, effective disease-modifying treatments remain limited, largely due to an incomplete understanding of the underlying immunopathology. Traditionally, sepsis has been viewed as a condition driven primarily by excessive inflammation; however, increasing evidence indicates that persistent immune dysregulation, rather than inflammation alone, underlies disease progression and poor outcomes.

Inflammation is an essential host defence mechanism, but its timely and active resolution is equally critical for restoring tissue homeostasis. Resolution of inflammation is now recognized as a highly regulated biological process governed by endogenous pathways, including specialized pro-resolving mediators, immune-cell reprogramming, efferocytosis of apoptotic cells, and restoration of tissue integrity. In sepsis, these resolution pathways are frequently impaired or uncoupled from inflammatory responses, resulting in sustained tissue injury, immune suppression, organ dysfunction, and increased susceptibility to secondary infections.

This review synthesizes current knowledge on the mechanisms of inflammation resolution and their relevance to sepsis. We discuss immune dysregulation in sepsis, cellular and molecular defects that impair resolution, and the role of specialized pro-resolving mediators such as lipoxins, resolvins, protectins, and maresins. Emerging evidence supporting the concept of sepsis as a “pro-resolution deficiency disorder” is critically evaluated. Finally, we highlight the therapeutic potential of resolution-based strategies that aim to restore immune balance rather than suppress inflammation. Targeting endogenous resolution pathways may represent a paradigm shift in sepsis management, offering new opportunities for improving outcomes in this complex and devastating condition.