Combining multi-omics analysis methods to identify biomarkers for mitophagy involved in immune checkpoint
Jian Yu1,2, Jiangtao Wang3, Xinya Liu4
1Department of Cardio-Oncology, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Background:
Immune checkpoint inhibitors (ICIs) are prone to induce cardiovascular adverse reactions during the immunotherapy of cancer patients, among which ICIs-related myocarditis is the most severe. Mitophagy dysregulation is associated with various heart diseases, but its role in ICIs-related myocarditis remains unclear.
Materials And Methods:
Mitophagy key genes in ICIs-related myocarditis were screened based on the single-cell RNA sequencing and bulk RNA sequencing data, and their expression levels and diagnostic value were verified. Meanwhile, the key genes, trajectory analysis and cell interaction were validated at the single-cell level. Finally, the myocardial injury markers, cardiac function indicators, histopathological analysis and mitophagy key genes were verified by constructing a mouse model of ICIs-related myocarditis.
Results:
A total of 4 mitophagy key genes in ICIs-related myocarditis were identified by combining multiple bioinformatics analysis methods: AW112010, Igfbp7, Tmsb4x, Ost4. The expression levels of mitophagy key genes in the ICIs-related myocarditis group were significantly higher than those in the normal group (P < 0.05 or P < 0.01), and both had high diagnostic value. Trajectory analysis and cell interaction results showed the interaction intensity and relative expression patterns among these 4 key genes. The ICIs-related myocarditis mouse model showed elevated myocardial injury markers (BNP, CK-MB, cTnT) and decreased cardiac function indicators (LVEDV, LVEF, LVIDd, LVIDs) compared to the normal group (P < 0.05 or P < 0.01). The pathological sections revealed obvious inflammation and damage in the myocardium of myocarditis group mice. Additionally, the qRT-PCR results indicated that the expression levels of AW112010, Igfbp7, Tmsb4x and Ost4 were significantly higher than those in the normal group (P < 0.05 or P < 0.01).
Conclusion:
Mitophagy is involved in the pathogenesis of ICIs-related myocarditis, and AW112010, Igfbp7, Tmsb4x and Ost4 may become potential biomarkers for future clinical practice.
