%0 Journal Article
%T Leveraging a neutrophil-derived PCD signature to predict and stratify patients with acute myocardial infarction: from AI prediction to biological interpretation.
%A Zhu Y
%A Chen Y
%A Zu Y
%J J Transl Med
%V 22
%N 1
%D 2024 Jul 2
%M 38956669
%F 8.44
%R 10.1186/s12967-024-05415-0
%X <B>BACKGROUND: </B>Programmed cell death (PCD) has recently been implicated in modulating the removal of neutrophils recruited in acute myocardial infarction (AMI). Nonetheless, the clinical significance and biological mechanism of neutrophil-related PCD remain unexplored.<BR><B>METHODS: </B>We employed an integrative machine learning-based computational framework to generate a predictive neutrophil-derived PCD signature (NPCDS) within five independent microarray cohorts from the peripheral blood of AMI patients. Non-negative matrix factorization was leveraged to develop an NPCDS-based AMI subtype. To elucidate the biological mechanism underlying NPCDS, we implemented single-cell transcriptomics on Cd45+ cells isolated from the murine heart of experimental AMI. We finally conducted a Mendelian randomization (MR) study and molecular docking to investigate the therapeutic value of NPCDS on AMI.<BR><B>RESULTS: </B>We reported the robust and superior performance of NPCDS in AMI prediction, which contributed to an optimal combination of random forest and stepwise regression fitted on nine neutrophil-related PCD genes (MDM2, PTK2B, MYH9, IVNS1ABP, MAPK14, GNS, MYD88, TLR2, CFLAR). Two divergent NPCDS-based subtypes of AMI were revealed, in which subtype 1 was characterized as inflammation-activated with more vibrant neutrophil activities, whereas subtype 2 demonstrated the opposite. Mechanically, we unveiled the expression dynamics of NPCDS to regulate neutrophil transformation from a pro-inflammatory phase to an anti-inflammatory phase in AMI. We uncovered a significant causal association between genetic predisposition towards MDM2 expression and the risk of AMI. We also found that lidoflazine, isotetrandrine, and cepharanthine could stably target MDM2.<BR><B>CONCLUSIONS: </B>Altogether, NPCDS offers significant implications for prediction, stratification, and therapeutic management for AMI.