Long non-coding RNAs in monocyte/macrophage-mediated immune dysregulation and organ injury in sepsis: mechanistic insights and therapeutic potential

Sepsis is a life-threatening organ dysfunction characterized by a dysregulated host response that oscillates between hyperinflammation and immunosuppression. Monocytes and macrophages are pivotal players in the immunopathogenesis of sepsis, driving both the initial cytokine storm and the subsequent state of immunosuppression. There remains an urgent need for new therapeutic approaches that effectively target monocytes and macrophages. As some of the most promising targets for RNA therapeutics (RNATx), which regulate molecular networks in a cell type-restricted manner, long non-coding RNAs (lncRNAs) are emerging as critical regulators of monocyte and macrophage functions, influencing their polarization and alterations during sepsis. This review systematically synthesizes current knowledge on how lncRNAs regulate the two immune states of sepsis—hyperinflammation and immunosuppression—in these monocytes and macrophages. We also examine the organ-specific effects of lncRNA-mediated macrophage dysfunction in sepsis-induced lung, liver, kidney, cardiac, and brain injury. By clarifying the molecular mechanisms of lncRNA action, we discuss their potential as therapeutic targets, providing insight into novel precision medicine strategies for sepsis management.