SAT-280 Finerenone Exerts Anti-Fibrotic Effects in the Liver of Mice with Hepatic Fibrosis Through TGF-β1 Expression and Activation

Abstract Disclosure: A. Feraco: None. A. Armani: None. C. Mammi: None. E. Bellucci: None. S. Gorini: None. E. Camajani: None. C. Quattrini: None. M. Lombardo: None. M. Caprio: Bayer, Inc.. The mineralocorticoid receptor (MR) activation plays a key role in various pathological conditions, including obesity, insulin resistance, and target organ fibrosis. We already showed that MR antagonism with finerenone improves metabolic parameters and activates brown adipose tissue in mice with diet-induced obesity. Metabolic-associated fatty liver disease (MASLD) is strongly associated with metabolic disorders and can progress to metabolic dysfunction-associated steatohepatitis (MASH), where fibrosis represents a critical complication. It is well established that pharmacological MR blockade acts as a potent anti-fibrotic agent in cardiovascular remodeling. We hypothesized that finerenone may offer therapeutic potential to mitigate hepatic inflammation and fibrosis in patients with MAFLD/MASH. Aim of this study was to investigate the hepatic effects of finerenone in a mouse model of liver fibrosis, i.e. db/db mice fed a diet deficient in methionine and choline (MCD), for 4 weeks. Finerenone did not affect food intake, but reduced body weight in mice on a control diet, highlighting important metabolic effects in diabetic mice. As already reported, MCD induced weight loss in db/db mice, and finerenone did not modify this effect. Liver histology analysis confirmed MASH features in MCD-fed mice, including macrovesicular steatosis and hepatocyte ballooning. Accordingly, Sirius Red staining, used to evaluate liver collagen deposition as a marker of fibrosis, revealed significantly increased collagen accumulation in MCD-fed mice compared to controls. Importantly, finerenone-treated mice fed the MCD diet displayed a trend of reduction in lipid accumulation, as revealed by Oil Red O staining, and significantly reduced Sirius Red staining intensity, highlighting a significant reduction in liver fibrosis. Finerenone induced a significant decrease in TGF-β1 mRNA expression, a central mediator of fibrosis progression. TGF-β1 is a key driver of ECM (extracellular matrix) protein synthesis. In finerenone-treated mice group, TGF-β1 pathway attenuation was further paralleled by increased mRNA and protein levels of MMP13, a matrix metalloproteinase critical for ECM degradation, suggesting that finerenone is able to promote ECM turnover and counteract fibrosis. Plasma samples were collected to analyze changes in lipoprotein subclasses and proinflammatory cytokines, in order to identify a potential signature of MASLD/MASH; this analysis is ongoing. The overall findings of this study emphasize finerenone’s robust effects in mitigating liver fibrosis in MCD-fed db/db mice, highlighting its potential as a novel therapeutic agent in MASH. Presentation: Saturday, July 12, 2025