A lipid–immune network signature defines susceptibility to asparaginase-associated pancreatitis

ABSTRACT: Asparaginase 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. To define early systemic features of susceptibility, we performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 159; 77 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and by the end of ALL induction therapy (which included a single induction dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. Across cohorts and analytic layers, we identify a reproducible lysophosphatidylcholine (LPC)–centered signature characterized by attenuated ALL induction therapy-associated LPC responses and disruption of LPC co-regulation at the network level. Proteomic profiling reveals concurrent enrichment of cytokine signaling pathways, and integrative analyses demonstrate altered lipid–cytokine coupling, including a flip in association direction for LPC species versus interleukin-18 (IL-18) between cases and controls. Although IL-18/LPC ratios do not differ globally, elevated post-induction IL-18/LPC ratios selectively identify AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81). These 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 prospective validation and network-informed mitigation strategies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Serum

SUBMITTER: Cheng-Yu Tsai  

LAB HEAD: Sohail Husain

PROVIDER: PAD000033 | Pride | 2026-03-31

REPOSITORIES: Pride