Role of lncRNAGAS5 and miR-146a in Regulating Inflammation and Wound Healing in Aging

Background: Long non-coding RNAs (lncRNAs) are gaining recognition as critical regulators of gene expression and cellular processes, including those involved in aging and tissue regeneration. Growth Arrest Specific 5 (GAS5) has been implicated in numerous biological functions, particularly in inflammation. Our previous research demonstrated that the upregulation of GAS5 in diabetic wounds prolongs inflammatory macrophage activation by inducing STAT1. However, its role in aging-related wound healing remains unexplored. Meanwhile, miR-146a, a small non-coding RNA associated with aging, plays a pivotal role in regulating cellular senescence, apoptosis, and inflammation. This study aims to investigate the interaction between GAS5 and miR-146a and their combined impact on aging-associated delays in wound healing. Methods: Aging-related wound healing was investigated using aged and young murine models. Wound tissue samples were analyzed for GAS5, miR-146a, and inflammatory marker gene expressions using qRT-PCR. The functional role of GAS5 and miR-146a was examined through overexpression and silencing experiments in vitro. Pro-inflammatory cytokine levels (IRAK1, TRAF6, and NF-κB) were measured using ELISA and qRT-PCR. The effects of miR-146a co-overexpression with GAS5 on ICAM1 expression were assessed using qRT-PCR and Western blotting. Results: Aged mice exhibited significantly delayed wound healing compared to young mice, with elevated GAS5 and ICAM1 expression levels, alongside reduced miR-146a expression. GAS5 overexpression upregulated ICAM1 expression, which was reversed by co-overexpression of miR-146a. Additionally, silencing GAS5 or overexpressing miR-146a in wound models led to a notable reduction in pro-inflammatory cytokine levels (IRAK1, TRAF6, and NF-κB). These findings highlight the regulatory axis of GAS5 and miR-146a in modulating inflammation and wound healing. Conclusion: Our findings suggest that GAS5 and miR-146a play opposing roles in regulating inflammation and wound healing in aged mice. Elevated GAS5 expression promotes inflammation via ICAM1, while miR-146a mitigates this effect, enhancing wound healing by targeting GAS5 and pro-inflammatory cytokines. Therapeutic strategies involving GAS5 silencing or miR-146a overexpression hold potential for improving wound healing outcomes in aging populations. National Institute of Health GM128660-01A1 to J Xu. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.