Comprehensive analysis and prediction model of mitophagy and ferroptosis in primary immune thrombocytopenia

Author:

Mo Jiani1,Liu Yong23,Zhang Wencong4,Li Liang3,Li Lindi3,Li Tianwen3,Mo Jiahua5,Chen Yujiang1,Liang Liang1,Zhang Yuming1,Yang Mo123ORCID

Affiliation:

1. Department of Hematology Affiliated Hospital of Guangdong Medical University (GDMU) Zhanjiang China

2. Scientific Research Center The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen Guangdong China

3. Pediatric Hematology Laboratory, Division of Hematology/Oncology, Department of Pediatrics The Seventh Affiliated Hospital of Sun Yat‐Sen University Shenzhen Guangdong China

4. Department of Orthopedics, Guangzhou Institute of Traumatic Surgery Guangzhou Red Cross Hospital, Medical College, Jinan University Guangzhou China

5. Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine Nanning China

Abstract

SummaryPrimary immune thrombocytopenia (ITP) is linked to specific pathogenic mechanisms, yet its relationship with mitophagy and ferroptosis is poorly understood. This study aimed to identify new biomarkers and explore the role of mitophagy and ferroptosis in ITP pathogenesis. Techniques such as differential analysis, Mfuzz expression pattern clustering, machine learning, gene set enrichment analysis, single‐cell RNA sequencing (scRNA‐seq) and immune infiltration analysis were employed to investigate the molecular pathways of pivotal genes. Two‐sample Mendelian randomization (TSMR) assessed the causal effects in ITP. Key genes identified in the training set included GABARAPL1, S100A8, LIN28A, and GDF9, which demonstrated diagnostic potential in validation sets. Functional analysis indicated these genes' involvement in ubiquitin phosphorylation, PPAR signalling pathway and T‐cell differentiation. Immune infiltration analysis revealed increased macrophage presence in ITP, related to the critical genes. scRNA‐seq indicated reduced GABARAPL1 expression in ITP bone marrow macrophages. TSMR linked S100A8 with ITP diagnosis, presenting an OR of 0.856 (95% CI = 0.736–0.997, p = 0.045). The study pinpointed four central genes, GABARAPL1, S100A8, LIN28A, and GDF9, tied to mitophagy and ferroptosis in ITP. It posits that diminished GABARAPL1 expression may disrupts ubiquitin phosphorylation and PPAR signalling, impairing mitophagy and inhibiting ferroptosis, leading to immune imbalance.

Funder

Basic and Applied Basic Research Foundation of Guangdong Province

Publisher

Wiley

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