Background: Hyperlipidemia (HLP) may intensify myocardial cell damage by disrupting lipophagy, a pivotal lipid metabolism pathway, thereby heightening the risk of acute myocardial infarction (AMI). This study aims to identify HLP- and lipophagy-associated biomarkers for AMI through a combined transcriptomic and Mendelian randomization (MR) approach. Methods: The mRNA expression data for AMI, along with HLP-related genes (HRGs) and lipophagy-related genes (LRGs), were sourced from public databases. Biomarkers were identified by conducting differential expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), MR analysis, and Receiver Operating Characteristic (ROC) analysis, complemented by two machine learning algorithms and expression validation. These biomarkers facilitated an investigation into the role of platelet activation-related genes (PARGs) in AMI, with enrichment analysis providing insights into their underlying mechanisms. Finally, reverse transcription-polymerase chain reaction (RT-PCR) was employed to validate biomarker expression in clinical samples. Results: Three biomarkers exhibited a consistently significant upregulation trend in AMI samples, corroborated by RT-qPCR findings. Notably, PLAUR [Odds Ratio (OR) = 1.115, 95% confidence interval (CI): 1.006-1.237, P = 0.038] and IVNS1ABP (OR = 1.047, 95% CI: 1.000-1.096, P = 0.048) emerged as AMI risk factors, while QKI (OR = 0.946, 95% CI: 0.903-0.991, P = 0.020) was identified as a protective factor. Additionally, PLAUR, QKI, and IVNS1ABP demonstrated robust diagnostic efficacy with Area Under the Curve (AUC) values of 0.773, 0.933, and 0.807, respectively; when integrated into a nomogram, the combined AUC reached 0.924. These genes were enriched in pathways linked to cardiovascular diseases, inflammatory responses, and cellular metabolic processes and appeared actively involved in platelet activation, as indicated by their strong associations with PARGs. Conclusion: In summary, the biomarkers PLAUR, QKI, and IVNS1ABP, connected to HLP and lipophagy, showed a causal relationship with AMI and marked diagnostic potential for predicting AMI risk, offering valuable support for clinical diagnostics and AMI research.

The authors have declared no competing interest.

This study was funded by Grants from the National Natural Science Foundation of China (82360077, 82460065), 535 Talent Project of First Affiliated Hospital of Kunming Medical University (2024535Q03), Yunnan Fundamental Research Projects (202201AU070063), Union Foundation of Yunnan Provincial Science and Technology Department and Kunming Medical University (202201AY070001-082).

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IRB of the First Affiliated Hospital of Kunming Medical University gave ethical approval for this work.

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