Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), closely linked to obesity and diabetes, remains poorly understood, with limited therapeutic options. The mineralocorticoid receptor (MR) has been implicated in metabolic dysregulation, yet its role in hepatic lipid metabolism remains incompletely defined. Finerenone, a non-steroidal MR antagonist, has demonstrated renal and cardiovascular benefits in diabetes , yet its effects on hepatic metabolism have not been fully explored. This study aimed to evaluate the hepatoprotective effects of finerenone in MASLD and elucidate the underlying mechanisms. MASLD models were established using db/db mice and free fatty acid-treated hepatocytes. Treatment with finerenone significantly reduced hepatic lipid accumulation in both in vitro and in vivo models. Mechanistically, MASLD was characterized by overactivation of hepatic MR signaling, evidenced by increased NR3C2 expression and upregulation of canonical MR target genes. Finerenone inhibits and antagonizes excessive MR activation, enhanced AMP-activated protein kinase (AMPK) phosphorylation, and downregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), thereby inhibiting de novo lipogenesis. The lipid-lowering effects of finerenone were abrogated by AMPKα knockdown or inhibition, while NR3C2 knockdown mimicked the metabolic effects of finerenone without additive benefit, supporting an MR-dependent mechanism. Conversely, aldosterone reversed the lipid-lowering effects of finerenone through the AMPK/SREBP1/FASN pathway. In conclusion, finerenone alleviates hepatic lipid accumulation in MASLD, at least in part, by inhibiting MR signaling and modulating the AMPK/SREBP1/FASN pathway. These findings highlight a previously underrecognized role of MR in hepatic lipid metabolism and support finerenone as a potential therapeutic strategy for MASLD.