Acta Biochimica et Biophysica Sinica · 9 authors, 3 centres
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This study identified a novel regulatory mechanism involving the lnc-5423.6/miR-193b-3p/IGFBP5 axis in early mouse thymic involution. RNA sequencing revealed that IGFBP5 expression increases during thymic involution and promotes apoptosis of thymic epithelial cells. The findings suggest that lnc-5423.6 acts as a molecular sponge for miR-193b-3p to upregulate IGFBP5, providing a potential target for delaying immune aging.
**Background:** The thymus is essential for T-cell production, and its age-related involution leads to immune senescence. The mechanisms underlying thymic involution, particularly the role of long noncoding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs), are not fully understood. This study aimed to identify lncRNA and mRNA expression profiles during early thymic involution in mice and to explore the regulatory role of the lnc-5423.6/miR-193b-3p/IGFBP5 axis.
**Methods:** Thymuses were collected from BALB/c mice at 1, 3, and 6 months of age (both sexes, n=15 per group). RNA sequencing was performed to identify differentially expressed lncRNAs (DELs) and genes (DEGs) using cutoffs of |log2(fold change)|>1 and P<0.05. GO and KEGG pathway analyses were conducted. A ceRNA network was constructed using miRWalk, TargetScan, and miRanda. Key interactions were validated in MTEC1 cells (mouse thymic epithelial cell line) using qRT-PCR, dual-luciferase reporter assays, CCK-8, EdU, flow cytometry, and western blot.
**Key Results:** A total of 21,521 lncRNAs and 46,699 genes were identified. Compared to 1-month-old mice, 3-month-old males had 439 DEGs and 440 DELs; 6-month-old males had 1,985 DEGs and 824 DELs. In females, 3-month-old had 262 DEGs and 323 DELs; 6-month-old had 442 DEGs and 308 DELs. Overlap analysis revealed 29 DELs common to both sexes at both involution stages. A ceRNA network comprising 29 lncRNAs, 145 miRNAs, and 12 mRNAs was constructed. IGFBP5 was significantly upregulated during involution. In MTEC1 cells, IGFBP5 overexpression reduced cell viability (CCK-8), decreased proliferation (EdU), and increased apoptosis (flow cytometry), with upregulation of p53, p21, and BAX. miR-193b-3p directly targeted the 3'UTR of IGFBP5 (dual-luciferase, P<0.01) and alleviated IGFBP5-induced apoptosis. lnc-5423.6 bound miR-193b-3p (dual-luciferase, P<0.01) and increased IGFBP5 expression, promoting apoptosis and inhibiting proliferation.
**Clinical Implications:** This study reveals a novel lnc-5423.6/miR-193b-3p/IGFBP5 ceRNA axis that promotes thymic epithelial cell apoptosis during early thymic involution. Targeting this axis may offer therapeutic strategies to delay thymic involution and improve immune function in aging. The data provide a foundation for further research on lncRNA-mediated regulation of thymic involution.