Long non-coding RNAs as key regulators in sepsis: from immune response to organ dysfunction

Sepsis remains a leading cause of morbidity and mortality in intensive care units worldwide, driven by a dysregulated host response to infection that culminates in multi-organ dysfunction. Current diagnostic biomarkers and therapeutic strategies lack the needed sensitivity, specificity and efficacy, underscoring an urgent need for novel molecular insights. Long non-coding RNAs (lncRNAs), a diverse class of transcripts exceeding 200 nucleotides without protein-coding capacity, have emerged as pivotal regulators of sepsis pathophysiology. They orchestrate immune responses, inflammatory cascades, cellular apoptosis, metabolic reprogramming and the lethal cross-talk among diverse cell death pathways. Through intricate interactions with DNA, RNA and proteins, lncRNAs also drive organ-specific injury via distinct cell-type specific mechanisms. Specific lncRNAs, including NEAT1, MALAT1 and GAS5, are deeply implicated in disease onset, progression and prognosis, highlighting their potential as both biomarkers and therapeutic targets. In this review, we synthesize current evidence on the roles of lncRNAs in immune modulation, organ dysfunction and metabolic regulation during sepsis. We also evaluate their promise in diagnosis, prognosis and therapy, and discuss major translational barriers, such as physicochemical instability, poor permeability and disease heterogeneity, that must be overcome for clinical application. A deeper understanding of these molecules may unlock novel strategies for the early diagnosis, prognosis, and treatment of sepsis.