Sepsis-associated efferocytosis deficiency: Molecular mechanisms and novel therapeutic targets

Despite advances in critical care, sepsis remains a leading cause of mortality driven by a profoundly dysregulated host immune response. Increasingly, defective efferocytosis-the fundamental physiological process for clearing dead cells-has been identified as a critical catalyst in sepsis pathophysiology. Under normal conditions, efferocytosis resolves inflammation and maintains tissue homeostasis. However, during sepsis, the efferocytotic capacity of phagocytes is severely paralyzed. This clearance failure results in a massive accumulation of apoptotic and necrotic cellular debris within the tissue microenvironment, triggering an unabated release of damage-associated molecular patterns (DAMPs). Consequently, this substrate overload sustains a self-amplifying inflammatory storm that accelerates tissue injury and precipitates multiple organ failure. In this review, we dissect the diverse modalities of programmed cell death in sepsis and map the subsequent breakdown of the core, multi-step efferocytotic machinery. We systematically explore the molecular basis of efferocytosis failure across distinct organ-specific complications, including acute lung injury, sepsis-associated encephalopathy, acute kidney injury, and septic cardiomyopathy. Finally, we evaluate emerging targeted therapies aimed at restoring efferocytotic efficiency, highlighting a crucial conceptual shift from primarily suppressing inflammation to actively promoting its resolution and repairing host immunity.