MRPL44 regulates lipid metabolism in metabolic dysfunction-associated steatotic liver disease through BNIP3-mediated mitophagy.

Objective: Mitophagy is a critical defense mechanism against metabolic dysfunction-associated steatotic liver disease. MRPL44, a mitochondrial ribosomal protein that regulates mitochondrial DNA-encoded gene expression, has not previously been linked to lipid metabolism. Methods: This study employed an oleic acid/palmitic acid induced HepG2 cell models and a high-fat diet fed mouse models, combined with lentivirus-mediated MRPL44 overexpression and mitophagy assays, to investigate the regulatory role of MRPL44 in the progression of metabolic dysfunction-associated steatotic liver disease. Results: Our findings demonstrated that MRPL44 alleviates lipid metabolic disorders induced by high-fat diet through the mitophagy pathway. Specifically, in oleic acid/palmitic acid-stimulated HepG2 cells, overexpression of MRPL44 reduced intracellular triglyceride accumulation and enhanced fatty acid oxidation. Moreover, liver-specific overexpression of MRPL44 in mice attenuated high-fat diet induced hepatic lipid deposition. Mechanistically, MRPL44 activated the BNIP3-dependent mitophagy pathway, promoted mitochondrial biogenesis, and mitigated mitochondrial damage, ultimately reducing lipid accumulation in hepatocytes. Conclusion: This study identifies MRPL44 as a novel regulator of lipid metabolism and a potential therapeutic target for metabolic dysfunction-associated steatotic liver disease.