# MALAT1 regulates human macrophage metabolism by interacting with HADHB

## TL;DR

This study shows how MALAT1, a noncoding RNA, interacts with HADHB to regulate metabolism in human macrophages, influencing inflammation.

## Contribution

The novel interaction between MALAT1 and HADHB in regulating macrophage metabolism during inflammation is uncovered.

## Key findings

- MALAT1 enhances HADHB thiolase activity via mitochondrial targeting by HuR-MTCH2.
- Knockdown of MALAT1 increases glycolysis and fatty acid synthesis while reducing fatty acid oxidation.
- MALAT1-HADHB interaction supports inflammation resolution by dampening pro-inflammatory activation.

## 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.

•MALAT1 binds HADHB to boost its thiolase activity in human macrophages•HuR-MTCH2 targets MALAT1 to mitochondria•MALAT1 dampens pro-inflammatory macrophage activation via HADHB•MALAT1-HADHB-driven metabolic switching supports inflammation resolution

MALAT1 binds HADHB to boost its thiolase activity in human macrophages

HuR-MTCH2 targets MALAT1 to mitochondria

MALAT1 dampens pro-inflammatory macrophage activation via HADHB

MALAT1-HADHB-driven metabolic switching supports inflammation resolution

Molecular mechanism of gene regulation; Cell biology; Metabolic flux analysis