Transl Pediatr. 2026 Mar 23;15(3):78. doi: 10.21037/tp-2025-aw-802. Epub 2026 Mar 18.
ABSTRACT
BACKGROUND: Hand, foot, and mouth disease (HFMD) complicated by encephalitis is a severe condition with an acute onset, yet its pathogenesis remains incompletely understood. This study aimed to investigate the role of platelet miR-223-3p in HFMD complicated by encephalitis. We sought to determine its expression dynamics, verify its direct target F-box and WD repeat domain containing 7 (FBXW7), and elucidate its functional impact on neuronal apoptosis, thereby exploring a novel microRNA (miRNA) mediated mechanism in the pathogenesis of this severe complication.
METHODS: We initially enrolled 20 children with HFMD complicated by encephalitis and 20 with uncomplicated HFMD. Platelet miRNA expression profiles were analyzed by high-throughput sequencing. Bioinformatics tools predicted key target genes, which were validated in a larger cohort (n=70) using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Gain- and loss-of-function models were established in SK-N-SH neuroblastoma cells by transfecting with an miR-223-3p mimic or inhibitor. A dual-luciferase reporter assay confirmed the direct targeting of FBXW7. The effects on apoptosis were assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and by measuring the protein levels of B-cell lymphoma 2 (Bcl-2), BCL2-associated X protein (Bax), and cleaved cysteinyl aspartate specific proteinase-3 (caspase-3) via Western blot. Rescue experiments with an FBXW7 overexpression plasmid (OE-FBXW7) were performed to confirm the specific pathway.
RESULTS: Platelet miR-223-3p was identified as the most significantly upregulated miRNA in the encephalitis group. Its expression was elevated in the acute phase but decreased during recovery (P<0.05). A significant negative correlation was observed between acute-phase miR-223-3p and whole-blood FBXW7 expression. Both messenger RNA (mRNA) and protein levels of FBXW7 were reduced by the miR-223-3p mimic and increased by its inhibitor (P<0.05). The dual-luciferase assay confirmed FBXW7 as a direct target. Functionally, miR-223-3p overexpression suppressed apoptosis, as evidenced by decreased TUNEL-positive cells, increased Bcl-2, and decreased Bax and cleaved caspase-3 (P<0.05). Conversely, both miR-223-3p inhibition and FBXW7 overexpression promoted apoptosis, and FBXW7 overexpression effectively reversed the anti-apoptotic effect of the miR-223-3p mimic.
CONCLUSIONS: Our study demonstrates that platelet miR-223-3p is significantly upregulated in HFMD complicated by encephalitis. It promotes the pathogenesis of this condition by directly targeting FBXW7 and inhibiting mitochondrial pathway-mediated apoptosis. These findings highlight a novel role for platelet miRNAs in the neuropathogenesis of HFMD and suggest the miR-223-3p/FBXW7 axis as a potential therapeutic target.
PMID:41982954 | PMC:PMC13071733 | DOI:10.21037/tp-2025-aw-802