Long non-coding RNAs as molecular hubs integrating inflammatory and osteogenic pathways in calcific aortic valve...

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Among valvular pathologies, CAVD is the most prevalent and poses a growing burden on the aging population. Once considered a passive degenerative process, aortic stenosis (AS) is now understood to be an actively regulated disease characterized by progressive leaflet fibrosis, calcification, and inflammation, ultimately leading to left ventricular outflow obstruction and heart failure. Current treatment options are limited to surgical or transcatheter valve replacement, as no pharmacological therapies exist to halt or reverse disease progression. This review frames the discussion around the potential of long non-coding RNAs (lncRNAs) as therapeutic targets, rather than implying established therapies.

Through the advancement of genetic manipulation techniques and their application in cardiovascular biology, non-coding RNAs have emerged as dynamic regulators of disease pathogenesis. While initial focus centered on microRNAs, recent evidence highlights lncRNAs as critical modulators of gene expression governing valvular interstitial cell (VIC) biology. LncRNAs influence key pathological processes in AS, including osteogenic differentiation, extracellular matrix remodeling, and inflammatory signaling. Furthermore, circulating lncRNAs, either freely circulating or encapsulated within extracellular vesicles, are emerging as novel mediators of intercellular communication within the valve microenvironment and represent promising candidates for diagnostic and prognostic applications, offering the potential for a liquid biopsy approach in AS management. Despite significant advancements in our understanding of non-coding RNA biology, the functional roles of specific lncRNAs in the pathogenesis of aortic stenosis remain largely unexplored. However, emerging evidence from related inflammatory pathways (e.g., NF-κB, MAPK, and JAK/STAT) and other cardiovascular diseases provides a rational basis for investigating the therapeutic potential of lncRNAs in AS, without overstating current knowledge. Elucidating the precise mechanisms by which lncRNAs regulate VIC fate and valvular calcification is crucial for the development of effective targeted interventions aimed at slowing or preventing disease progression and reducing the clinical burden of AS.

Key unanswered questions remain: What is the specific lncRNA signature of CAVD? How do individual lncRNAs functionally contribute to disease progression? And how can the delivery and targeting challenges associated with lncRNA-based therapeutics be overcome? This review provides a comprehensive landscape of the current developmental progression of RNA therapeutics, with a specific focus on lncRNA-based strategies as a holistic approach for treating CAVD in preclinical models. Addressing these research priorities will be essential for translating lncRNA-based strategies into clinical applications for this increasingly prevalent disease.