Advances in understanding the mechanism of noncoding RNA (ncRNA)-mediated regulation of macrophage polarization in NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD), recently reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as the most prevalent chronic liver disorder worldwide, progressing from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Increasing evidence highlights the pivotal role of immune-inflammatory responses in NAFLD pathogenesis, with macrophage polarization serving as a key regulatory mechanism that influences disease initiation, progression, and potential resolution. Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as essential modulators of macrophage phenotype and function by influencing transcriptional checkpoints, inflammatory signaling pathways, and intercellular communication. Recent findings further underscore the role of lipotoxicity-associated ncRNAs in transmitting stress signals from hepatocytes to macrophages, thereby amplifying immune dysregulation and fibrogenesis. This review summarizes current knowledge on ncRNA expression and function in NAFLD, with a focus on their regulatory roles in macrophage polarization across disease stages, from steatosis to HCC. We categorize ncRNA-targeted therapies into specific approaches (e.g., miRNA mimics or inhibitors) and nonspecific interventions (e.g., exosome- or compound-mediated modulation), and further discuss their therapeutic potential and challenges, as well as emerging macrophage-targeted delivery systems. By linking molecular mechanisms to therapeutic strategies, we propose ncRNA-based modulation of macrophage polarization as a promising avenue for the diagnosis and treatment of NAFLD.