LAUSR

AIMS The incidence of calcific aortic valve disease (CAVD) has risen over the last decade and is expected to continue rising; however, pharmacological approaches have proven ineffective. In this study, we evaluated the role and underlying mechanisms of human antigen R (HuR)-mediated post-transcriptional regulation in CAVD. METHODS AND RESULTS We found that HuR was significantly upregulated in human calcified aortic valves and primary aortic valvular interstitial cells (VICs) following osteogenic stimulation. Subsequent functional studies revealed that HuR silencing ameliorated calcification both in vitro and in vivo. For the first time, we demonstrated that HuR directly interacted with the transcript of phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A), which mediates phosphatidylinositol signaling, facilitates autophagy, and act as an mRNA stabilizer. HuR positively modulated PIP4K2A expression at the post-transcriptional level, and consequently influenced the AKT/mTOR/ATG13 pathway to regulate autophagy and CAVD progression. CONCLUSION Our study provides new insights into the post-transcriptional regulatory role of HuR in modulating autophagy-positive factors to regulate the pathogenesis of CAVD. Our findings highlight the potential of HuR as an innovative therapeutic target in CAVD treatment. TRANSLATIONAL PERSPECTIVE As the incidence of CAVD has been rising over the past decade with only invasive, expensive, and risky interventions available, it is imperative to explore novel approaches to halt aortic valve calcification. Currently, regulation of CAVD pathogenesis is not fully understood. HuR, an RNA-binding protein, and autophagy are thought to play key roles in CAVD; however, the precise underlying mechanisms have not been elucidated. Therefore, we believe that the findings of this study are relevant to the field because they provide direct evidence of a critical role for HuR, hVIC phenotypic transition, and autophagy in CAVD and suggest a novel target for hindering CAVD progression.