Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in systemic diseases; however, their role in severe malarial anaemia (SMA) remains poorly defined. In this study, we applied an integrative systems biology approach using paediatric RNA sequencing data (GSE255403) and EV-associated protein datasets (ExoCarta) to explore potential links between host transcriptional responses and EV-related molecular features. We identified a coordinated six-gene transcriptional signature (TFRC, CD274, BSG, PRDX2, SLC16A1, HSPA1A) showing strong co-expression (Pearson correlation r = 0.74–0.95) and involvement in key biological processes including iron homeostasis, immune regulation, oxidative stress, metabolism, and host–parasite interaction. Network and co-expression analyses suggest that these genes form a functionally connected module. While the association with EV biology is inferred from curated datasets and does not directly demonstrate vesicular origin or function, the findings highlight a potential link between intracellular transcriptional changes and extracellular signalling pathways in SMA. Independent validation using the GSE1124 microarray dataset further supports the reproducibility of the identified transcriptional signature. Overall, this study provides a hypothesis-generating framework for investigating EV-related mechanisms in SMA pathogenesis. M.S.S. and A.W. contributed equally to this work.
Shukla et al. (2026) studied this question.