Circulating Lipids Predict Mortality and Drive Immune Gene Regulation in Acute-on-Chronic Liver Failure

Background: Acute-on-chronic liver failure (ACLF) has ~ 50% 28-day mortality driven by systemic inflammation, immune dysfunction, and multiorgan failure. The contribution of circulating lipids to ACLF pathogenesis remains poorly understood. We investigated whether plasma lipid signatures predict short-term mortality and participate in immune dysregulation in ACLF. Methods: Targeted plasma lipidomics was performed in ACLF patients (n = 100; discovery n = 60, validation n = 40) and healthy controls (n = 40). Prognostic utility of lipid signatures was compared with MELD, MELD-Na, and CTP scores. Cross-disease lipidome comparisons, ex vivo lipid-leukocyte assays, proteomic profiling of neutrophils and post-mortem liver/kidney tissue, and in silico docking were used to investigate mechanistic relevance. Results: Of 1218 quantified lipids, 316 were altered in ACLF and 30 were validated in an independent cohort. A five-lipid mortality signature [LPE(18:2), LPE(20:4), PE(O-18:0/16:1), TAG(48:1/16:1), PE(P-18:2/18:2)] discriminated survivors from non-survivors, with AUROC values comparable to MELD-Na and CTP. A combined lipid-CTP logit model achieved AUROC of 0.912, outperforming individual clinical scores. ACLF lipid profiles overlapped with those of sepsis, trauma, and COVID-19, indicating conserved critical-illness biology. Ex vivo , ACLF-derived lipids downregulated TLR1/6/7/8/10 and induced CD177 in healthy leukocytes, recapitulating ACLF-like immune signatures. Proteomic analyses across neutrophils, liver, and kidney revealed a shared neutrophil-degranulation program, while in vitro assays showed that ACLF lipids were cytotoxic to HEK293T cells. In silico docking demonstrated potential binding of ACLF-lipids with PPARγ with affinities comparable to known ligands, suggesting a transcriptional mechanism linking lipid alterations to immune gene regulation. Conclusion: Circulating lipids in ACLF serve dual roles as prognostic biomarkers and active mediators of immune dysfunction and tissue injury. A validated five-lipid signature accurately predicts 28-day mortality, and mechanistic analyses implicate lipid-driven PPARγ modulation, TLR suppression, and neutrophil activation in ACLF pathogenesis. These findings offer opportunities for lipid-based risk stratification and therapeutic targeting in ACLF.