A recent study published in Genes & Diseases by researchers from Chongqing Medical University and Chongqing University Central Hospital identified salt-inducible kinase 1 (SIK1) as a pivotal protective gene that suppresses EV-D68–induced asthma by enhancing antiviral immunity and modulating airway inflammation.

Using a multi-omics and machine-learning framework, the researchers analyzed transcriptomic datasets from EV-D68 infection and clinical asthma cohorts, identifying 74 shared differentially expressed genes associated with both conditions. Through LASSO regression, SVM-RFE, Random Forest, and XGBoost ranking, SIK1 consistently emerged as the top signature gene associated with asthma susceptibility. Mendelian randomization further revealed a significant negative causal relationship between SIK1 expression and asthma risk, suggesting that higher SIK1 levels may protect against asthma development.

Immune infiltration analyses demonstrated that SIK1 expression correlated positively with antiviral and adaptive immune cell subsets—including activated CD4 memory T cells, follicular helper T cells, and activated dendritic cells—while showing negative associations with mast cells, naïve B cells, and M2 macrophages.

Weighted gene co-expression network analysis identified SIK1 within modules enriched for NF-κB, JAK-STAT, Toll-like receptor, and IL-17A signaling pathways, implicating it in both innate antiviral defense and T-cell–mediated adaptive immunity.

Functional validation confirmed that SIK1 expression is strongly induced by viral infection in vitro and in vivo. Across multiple viruses—including EV-D68, EV-A71, HSV-1, VSV-GFP, SARS-CoV-2, and CV-A6—SIK1 was consistently up-regulated. Silencing SIK1 dramatically increased viral replication, while SIK1 overexpression significantly suppressed viral load. These findings establish SIK1 as a broad-spectrum antiviral effector.

In a mouse model of EV-D68–induced asthma exacerbation, activation of SIK1 using metformin markedly reduced eosinophilic and neutrophilic airway inflammation, decreased type 2 cytokines IL-5 and IL-13, improved airway hyper-responsiveness, and lowered viral burden, while boosting antiviral CXCL10 expression.

Together, these findings position SIK1 as a central host-protective factor capable of simultaneously enhancing antiviral immunity and limiting inflammatory damage. Targeting SIK1 or its upstream regulatory pathways may provide a new therapeutic strategy for virus-induced asthma exacerbations.

Reference

Title of Original Paper
Salt-inducible kinase 1 is a key gene in suppressing EVD68-induced asthma by modulating antiviral immunity

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.2025.101845

Funding Information:

• The National Natural Science Foundation of China (No. 31600139)
• The Chongqing Municipal Education Commission of China (No. CSTB2024NSCQ-KJFZMSX0067)
• The Project of Undergraduates Innovating Experiment and the Project of Tutorial System of Excellent Medical Undergraduate in Lab Teaching and Management Center of Chongqing Medical University (China) (No. 202211, No. S202410631068, No. 202510631005, No. LTMCMTS202310, No. LTMCMTS202311, No. LTMCMTS202312, No. LTMCMTS202458, No. LTMCMTS202459, No. LTMCMTS202460, No. LTMCMTS202461)
• The Program for Youth Innovation in Future Medicine, Chongqing Medical University (China) (No. W0160)
• The Chongqing Medical Scientific Research Project (Joint Project of Chongqing Health Commission and Science and Technology Bureau (No. 2024ZDXM011)
• The Natural Science Foundation of Chongqing, China (No. CSTB2023NSCQ-MSX0237)

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