Mineralocorticoid receptor antagonists for liver fibrosis: Potential mechanisms and research progress
image: Reversing and treating liver fibrosis remain major challenges in hepatology, and currently, there is a lack of ideal antifibrotic drugs. Based on the pivotal role of the aldosterone–MR pathway in inflammation and fibrosis, MRAs constitute a novel therapeutic approach for antifibrotic treatment. Preclinical data consistently demonstrate that MRAs suppress HSC activation, oxidative stress, and inflammatory remodeling while restoring metabolic balance. New-generation nsMRAs, especially finerenone, combine potent antifibrotic and anti-inflammatory properties with superior receptor selectivity and safety. Although the current evidence is derived mainly from cardiorenal studies and small MASH trials, these findings underscore their translational potential in liver disease. Clinically, translating these findings will require careful patient stratification (e.g., metabolic vs. cholestatic etiologies), selection of appropriate endpoints (including histological improvement, validated noninvasive fibrosis markers, and portal pressure), and integration with existing standards of care. In addition, the use of MRAs in liver disease should include safety monitoring strategies, particularly for hyperkalemia, renal function, and drug–drug interactions, especially in patients with advanced fibrosis or cirrhosis. In the future, more studies are needed to evaluate the use of nsMRAs in various liver disease settings, including investigations of their pharmacokinetics, efficacy, and safety in advanced fibrosis. Well-designed randomized controlled trials specifically targeting liver fibrosis are essential to define the therapeutic positioning of MRAs, including their potential role in combination regimens with metabolic, anti-inflammatory, or antifibrotic agents. In conclusion, MRAs, particularly finerenone, may become an important component of combination therapy strategies for liver fibrosis, offering a potential therapeutic option for patients with chronic liver disease.
Credit: Ye Feng
Liver fibrosis is a common outcome of chronic liver injury and a determinant of cirrhosis and hepatic failure. Effective antifibrotic strategies remain limited. MR (NR3C2) has emerged as a central regulator of hepatic homeostasis, expressed across multiple liver cell types. MR signalling is dysregulated in fibrosis via ligand‑dependent (aldosterone excess) and ligand‑independent mechanisms (hypoxia), activating profibrotic pathways. This review summarises MR biology, mechanisms in fibrosis, and preclinical/clinical evidence for MRAs.
MR Structure and Pharmacology
MR is a nuclear receptor with N‑terminal modulatory, DNA‑binding, and ligand‑binding domains. Inactive MR resides in cytoplasm; ligand binding induces nuclear translocation and coregulator recruitment. MR activation is not strictly ligand‑dependent—hypoxia, oxidative stress, and metabolic injury also promote nuclear localisation.
MRAs are orthosteric competitive antagonists. Distinct ligands stabilise different MR conformations, altering transcription. Classical steroidal MRAs (spironolactone, eplerenone) may show partial agonism. Nonsteroidal MRAs (finerenone) induce alternative conformations, impair coactivator binding, and show inverse agonist activity.
Traditional MRAs
Spironolactone and eplerenone are used for heart failure and hypertension. RALES confirmed spironolactone reduced mortality in severe heart failure; EPHEsUS showed eplerenone reduced post‑infarction mortality. However, spironolactone lacks selectivity, causing gynaecomastia and menstrual irregularities. Both carry hyperkalaemia risk, limiting use.
Nonsteroidal MRAs
Finerenone has high MR affinity and selectivity, with negligible affinity for other steroid receptors. Apararenone is a nonsteroidal 1,4‑benzoxazin‑3‑one with high selectivity. Finerenone is short‑acting (~2–3 h), apararenone long‑acting (~275 h). Both rarely cause endocrine effects. Finerenone has balanced cardiac/renal distribution and reduced hyperkalaemia risk.
Clinical Evidence
Steroidal MRAs improve survival in heart failure. Finerenone has shown consistent cardiorenal protection in large RCTs, approved for type 2 diabetes and chronic kidney disease, with superior safety versus steroidal MRAs.
Pathological Activation of MR in Liver Fibrosis
MR activation drives fibrosis through interconnected pathways:
-
TGF‑β amplification: MR upregulates TGF‑β1/Smad signalling, promoting HSC activation and ECM deposition; increases TIMP‑1, suppressing ECM degradation.
-
Oxidative stress: MR enhances NADPH oxidase‑derived ROS, amplifying TGF‑β and NF‑κB signalling.
-
Inflammation: MR activates NF‑κB and NLRP3, promoting TNF‑α and IL‑6.
-
Metabolic dysregulation: MR disrupts PPARα and lipid oxidation, contributing to steatosis.
These pathways are interconnected; MR functions as a central hub coupling metabolic injury, immune activation, and ECM remodelling. Systemic regulators include RAAS and adipokines (leptin/adiponectin imbalance).
Cell‑type mechanisms:
-
HSCs: MR promotes transdifferentiation via TGF‑β/Smad; blockade suppresses activation.
-
Macrophages: MR promotes M1 polarisation and inflammasome activation.
-
Hepatocytes: MR promotes lipotoxicity, oxidative stress, and NF‑κB signalling.
-
LSECs: MR drives capillarisation via Cav1‑dependent oxidative stress; antagonism reverses this.
Preclinical and Clinical Evidence
Preclinical: Steroidal MRAs reduce collagen deposition and HSC activation in toxin/immune models. Eplerenone inhibits HSC activation and TIMP‑1. Effects are most consistent in cholestatic/toxin models; NASH models show variable responses.
Clinical: A phase II trial of apararenone in MASH showed trends toward fibrosis improvement but did not meet its primary endpoint. Finerenone evidence comes from cardiorenal trials showing no worsening of liver enzymes, with safety comparable to placebo. These studies were not designed to assess liver fibrosis. Current data support safety but not fibrosis regression.
Advantages and Challenges
Advantages: Multi‑target anti‑inflammatory, antioxidative, antifibrotic effects; systemic cardiorenal benefits; nsMRAs have better safety profiles.
Challenges: Limited pharmacokinetic data in advanced liver disease; no RCTs specifically evaluating finerenone for liver fibrosis; efficacy may differ by aetiology.
Conclusions
MRAs constitute a novel antifibrotic approach. Preclinical data show suppression of HSC activation, oxidative stress, and inflammation. New‑generation nsMRAs, especially finerenone, combine potent antifibrotic properties with superior selectivity and safety. Clinical translation requires patient stratification, appropriate endpoints, and safety monitoring. Future RCTs specifically targeting liver fibrosis are essential to define the therapeutic positioning of MRAs, including combination regimens.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2026-00019
The study was recently published in the Journal of Clinical and Translational Hepatology.
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
Follow us on X: @xiahepublishing
Follow us on LinkedIn: Xia & He Publishing Inc.