CircRNA hsa_circ_0001946 promotes hypertrophic scar pathogenesis via the miR-514a-3p/COL5A2 axis.

Abstract

Hypertrophic scars (HSs) represent a fibroproliferative disorder characterized by excessive extracellular matrix deposition. However, the underlying regulatory mechanisms involving circular RNAs (circRNAs) have not yet been fully elucidated. This study aimed to delineate the circRNA expression landscape in HS and reveal the functional roles of a specific candidate circRNA through the competing endogenous RNA (ceRNA) network. Eighty-one differentially expressed circRNAs (DEcircRNAs) were identified in five paired HS and normal skin samples by high-throughput sequencing. Functional enrichment analysis of host genes highlighted pathways involving cell proliferation and ECM-receptor interactions. CircRNA-miRNA-mRNA network analysis revealed hsa_circ_0001946 as a significantly upregulated candidate circRNA. Subsequent RT-qPCR validated its elevation in human HS tissues and hypertrophic scar fibroblasts (HSFs). Subcellular fractionation and RNase R assays confirmed its cytoplasmic localization and circular stability. Functionally, knockdown of hsa_circ_0001946 significantly inhibited HSF proliferation, migration, and collagen gel contraction. Mechanistically, dual-luciferase reporter assays demonstrated that hsa_circ_0001946 acts as a sponge for miR-514a-3p; notably, silencing hsa_circ_0001946 attenuated the pro-fibrotic effects induced by miR-514a-3p inhibition. Furthermore, miR-514a-3p was shown to directly target and suppress COL5A2. Collectively, these findings establish that hsa_circ_0001946 promotes HS development by sequestering miR-514a-3p to derepress COL5A2 expression. This study identifies the hsa_circ_0001946/miR-514a-3p/COL5A2 axis as a novel pathogenic mechanism contributing to HS formation, suggesting hsa_circ_0001946 as a promising intervention target for mitigating pathological scarring.