piR-hsa-022095 Drives Hypertrophic Scar Formation via KLF11-Dependent Fibroblast Proliferation

Background/Objectives: Hypertrophic scar (HS) is a fibroproliferative disorder characterized by excessive fibroblast activation and collagen deposition. The role of PIWI-interacting RNAs (piRNAs) in HS pathogenesis has not been defined. This study aimed to identify HS-related piRNAs, clarify their molecular mechanisms, and evaluate their therapeutic potential. Methods: High-throughput piRNA sequencing was performed on hypertrophic scar and matched normal tissues, followed by validation in patient-derived samples and dermal fibroblasts using quantitative reverse transcription PCR. Functional assays, including proliferation, apoptosis, migration, and invasion assays, were conducted after transfection with piRNA mimics or inhibitors. RNA sequencing, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, as well as dual-luciferase reporter and rescue assays, were used to identify and confirm molecular targets. Results: Sequencing revealed piR-hsa-022095 as one of the most significantly upregulated piRNAs in HS. Its inhibition suppressed fibroblast viability, migration, and invasion while inducing apoptosis and G₀/G₁ arrest. Transcriptomic profiling identified cell-cycle-related genes as major downstream targets, with KLF11 emerging as the principal effector. piR-hsa-022095 targets the 3' UTR of KLF11, repressing its expression and thereby facilitating fibroblast proliferation. Restoration of KLF11 reversed the pro-fibrotic effects of piR-hsa-022095, confirming its functional role in HS pathogenesis. Conclusions: This study identifies piR-hsa-022095 as a novel regulator implicated in HS formation through repression of KLF11. The piR-hsa-022095-KLF11 axis may represent a previously unrecognized regulatory pathway involved in hypertrophic scar formation, providing new insights into the molecular mechanisms underlying HS pathogenesis.