In a recent Genes & Diseases study, researchers from Lanzhou University, The First Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Fudan University, Massachusetts General Hospital and Harvard Medical School, and The First Affiliated Hospital of Nanjing Medical University utilized an integrated multiomic approach—incorporating data from the Global Burden of Disease Study 2021, Mendelian randomization (MR), and machine learning—to clarify the relationship between alcohol use and epilepsy and to identify the underlying molecular mechanisms.

Integrated genomic and population-level analyses provide evidence for a causal relationship between alcohol consumption and epilepsy risk. Mendelian randomization and global disease burden datasets indicate that alcohol consumption significantly elevates epilepsy risk, reinforcing the need to elucidate the underlying biological mechanisms.

Comprehensive multiomic approaches, incorporating machine learning, protein–protein interaction networks, and pathway enrichment analyses, identified neutrophil extracellular trap (NETs) formation as a key biological process linking alcohol exposure to epileptogenesis. Utilizing three machine learning algorithms—LASSO, random forest (RF), and SVM-RFE—the study identified a consensus set of hub genes, specifically MPO and neutrophil elastase (ELANE), as key regulatory nodes, suggesting that innate immune activation and neutrophil-driven responses contribute to neuronal hyperexcitability. Functional enrichment analysis highlights inflammatory and immune-related pathways associated with NET release, underscoring the role of these extracellular structures in mediating neurotoxicity and seizure susceptibility.

Experimental validation using murine models further corroborated these findings. The study demonstrated that acute alcohol exposure significantly upregulates MPO protein expression in the hippocampus of both normal mice and those in chronic (kainic acid-induced) or acute (pentylenetetrazol-induced) epilepsy models. In contrast, the expression of ELANE remained unchanged. Behavioral tests revealed that while acute alcohol exposure shortens seizure latency, pretreatment with the MPO inhibitor 4-aminobenzoic acid hydrazide (4-ABAH) significantly prolongs this latency, suggesting that MPO activity facilitates alcohol-induced seizure susceptibility.

MPO inhibition reduces the oxidative stress burden and limits NET-associated inflammatory damage, thereby mitigating neuronal excitability and seizure propensity, suggesting that targeting the NET pathway offers a viable therapeutic strategy for alcohol-induced epilepsy.

Collectively, these findings establish that alcohol exposure promotes epilepsy risk through MPO-mediated NET formation, integrating immune activation, oxidative stress, and neuronal dysfunction. This study highlights the research value of multiomic strategies in unraveling complex disease mechanisms and supports the therapeutic potential of targeting NET-related pathways to prevent or reduce alcohol-associated epileptogenesis.

Reference

Title of the original paper: Multiomic insights into the MPO-mediated NET formation pathway in alcohol-induced epilepsy risk

Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101917

Funding Information:

1. National Natural Science Foundation of China (No. 82160262, 82571663, 82001378)
2. General Project of Gansu Province Joint Research Fund (China) (No. 23JRRA1504)
3. Major Scientific Research Projects of Scientific and Technological Innovation in Health Industry of Gansu Province in 2025 (China) (No. GSWSZD2025-12)
4. Natural Science Foundation of Chongqing (China) (No. CSTB2023NSCQ-JQX0035, CSTB2022NSCQ-LZX0038)
5. Chongqing Postdoctoral Research Project Special Funding (No. 2023CQBSHTBT001).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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