A lipid-immune network signature defines susceptibility to asparaginase-associated pancreatitis.
BACKGROUNDAsparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP.METHODSWe performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses and integrated lipid-cytokine associations using proteomics.RESULTSAcross cohorts, we identified a reproducible lysophosphatidylcholine-centered (LPC-centered) signature characterized by attenuated induction therapy-associated LPC responses and disruption of LPC coregulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid-cytokine coupling, including a flip in association direction for LPC species and IL-18 between cases and controls. Although IL-18/LPC ratios did not differ globally, elevated postinduction IL-18/LPC ratios identified AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81).CONCLUSIONThese findings support a systems-level model in which failure of coordinated lipid-immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies.TRIAL REGISTRATIONNCT00400946; NCT01574274; NCT03020030 (parent trials).FUNDINGServier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Québec - Santé; Fondation Charles-Bruneau; Leukemia & Lymphoma Society of Canada.