ApoA1/HDL and sepsis-associated vascular endothelial injury: a narrative review

Sepsis remains a leading cause of global mortality, primarily driven by microvascular collapse stemming from severe vascular endothelial injury. Within this pathology, the dramatic depletion of Apolipoprotein A1 (ApoA1) and its carrier, high-density lipoprotein (HDL), is a hallmark feature. Despite being recognized as a prognostic biomarker, a comprehensive understanding of the ApoA1/HDL axis as an active participant and therapeutic target in endothelial protection remains fragmented. This review systematically synthesizes current evidence to reframe the ApoA1/HDL axis from a passive indicator to a master regulator of endothelial homeostasis in sepsis. We first delineate the strong correlation between reduced ApoA1/HDL levels and endothelial damage across various infections. Subsequently, we dissect its protective triad of mechanisms: potent anti-inflammatory actions, preservation of endothelial barrier integrity, and restoration of microvascular flow. Furthermore, we explore the emerging interplay between ApoA1 and exosomes, a novel aspect of its regulatory function. Finally, the translational potential of ApoA1-based therapies, including mimetic peptides and recombinant HDL, is evaluated. By providing an integrated mechanistic framework, this review highlights the ApoA1 as a critical therapeutic target and offers a roadmap for developing novel, endothelium-centric treatments for sepsis.