GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE337nnn/GSE337589/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE337589GEOGSEfalseMicroRNA-34a Promotes Hepatic Lipid Accumulation through RXRα Suppression and Is Reversed by 9-cis-Retinoic Acid in Steatotic HepatocytesMetabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide and is characterized by excessive hepatic lipid accumulation and metabolic dysregulation. Although microRNA-34a (miR-34a) has been implicated in lipid metabolism, the molecular mechanisms underlying its contribution to MAFLD remain incompletely understood. This study aimed to investigate the role of miR-34a in hepatic steatosis and to identify potential therapeutic targets. An in vitro steatosis model was established using free fatty acid (FFA)-treated HepG2 cells. miR-34a expression was analyzed by RT-qPCR, and direct target interactions were validated using dual-luciferase reporter assays. Proteomic alterations were characterized by iTRAQ-based proteomic profiling, followed by Ingenuity Pathway Analysis (IPA). The therapeutic potential of retinoid X receptor alpha (RXRα) activation was evaluated using 9-cis-retinoic acid (9-cis-RA). miR-34a expression was significantly increased in FFA-treated hepatocytes and directly targeted the 3′-UTRs of PPARα, SIRT1, and RXRα. Integrated transcriptomic and proteomic analyses identified LXR/RXR signaling as a major pathway disrupted by miR-34a overexpression. RXRα was validated as a direct downstream target of miR-34a, establishing a mechanistic link between microRNA dysregulation and nuclear receptor signaling. Pharmacological activation of RXRα by 9-cis-RA markedly attenuated lipid accumulation and reduced the expression of key lipogenic and fatty acid uptake proteins, including FASN, SCD1, and CD36. Our findings identify RXRα as a novel target of miR-34a and reveal a previously unrecognized miR-34a–RXRα regulatory axis governing hepatic lipid homeostasis. Activation of RXRα effectively reverses steatotic phenotypes, highlighting the miR-34a–RXRα axis as a potential therapeutic target for MAFLD.2026/07/15GSE337589GSM9858239GSM985824034284337589Homo sapiens