Abstract
Long noncoding RNAs (lncRNAs) are critical regulators of immune responses and cellular metabolism. Here, we report a previously unrecognized interaction between MALAT1 and HADHB, which reveals additional regulatory roles for MALAT1 in human macrophages. Our findings demonstrate that MALAT1-HADHB interaction significantly enhances HADHB thiolase activity during the late phase of inflammation via HuR-MTCH2-mediated mitochondrial targeting of MALAT1. MALAT1 also negatively regulates the pro-inflammatory macrophage activation via HADHB. Knockdown of MALAT1 induces metabolic reprogramming, characterized by enhanced glycolysis, increased fatty acid synthesis, and reduced fatty acid oxidation, suggesting that MALAT1 suppresses inflammatory metabolic pathways. This study uncovers the MALAT1-HADHB interaction and demonstrates that MALAT1 regulates macrophage metabolic reprogramming, offering new insights into the metabolic control of inflammation and highlighting MALAT1 as a potential therapeutic target for inflammatory diseases.