Plasma LCP1–HRG contrast and sepsis mortality: LCP1 knockdown attenuates inflammasome-associated lytic responses in THP-1 cells

Background Lymphocyte cytosolic protein 1 (LCP1; L-plastin) and histidine-rich glycoprotein (HRG) represent distinct aspects of immune-cell biology and circulating protein homeostasis. We examined whether a standardized contrast between these proteins was associated with sepsis mortality and investigated the effect of intracellular LCP1 knockdown on inflammasome-associated injury in THP-1 cells. Methods Exploratory plasma-proteomic screening in PXD051271 and PXD055932 informed selection of LCP1 and HRG. An equal-weight contrast, z [z (LCP1) − z (HRG)], was evaluated in the PXD051271 train, test, validation, and auxiliary HERO populations and in the separate PXD055932 source study. Logistic models estimated 30-day mortality associations, and five-fold cross-validation within each population assessed incremental discrimination. Paired day-1/day-4 plasma measurements were examined descriptively. Four whole-blood transcriptomic cohorts and single-cell data from seven participants provided complementary transcriptional context. LCP1-knockdown THP-1 cells were evaluated after LPS priming and ATP challenge by quantitative PCR, ELISA, ASC imaging, caspase-1 FLICA/propidium iodide flow cytometry, LDH release, and CCK-8, with MCC950 comparison and an LCP1-rescue condition. Results The contrast was associated with 30-day mortality in the three internal populations (adjusted odds ratios per standard deviation, 2.10, 2.18, and 2.01) and in PXD055932 (adjusted odds ratio, 1.78). Its incremental AUC was approximately 0.011 when cross-validation was performed within PXD055932 using SOFA, sex, and batch as baseline covariates. LCP1 and HRG were weakly correlated in the internal train and test populations. Whole-blood LCP1 mortality effects were heterogeneous and nonsignificant in random-effects meta-analysis. Single-cell data showed prominent monocyte LCP1 expression, but participant-level priming and damage-context trends did not meet the false-discovery threshold, and the pyroptosis-execution-associated set was not enriched. LCP1 knockdown modestly reduced LPS-induced transcripts and attenuated ATP-associated ASC-speck positivity, caspase-1-associated FLICA/PI responses, LDH release, and IL-1β secretion. The LCP1-rescue condition recovered these responses to different extents. Conclusion An exploratory LCP1–HRG plasma contrast is associated with sepsis mortality across two source studies, with limited additional discrimination beyond clinical covariates. Intracellular LCP1 contributes to inflammasome-associated lytic responses in THP-1 cells.