Finerenone Attenuates Peritoneal Fibrosis by Restoring Autophagy Flux

Peritoneal fibrosis (PF) is a progressive complication of long-term peritoneal dialysis, driven primarily by high-glucose-induced mesothelial injury, epithelial-mesenchymal transition, and chronic inflammation. Emerging evidence implicates autophagy dysfunction as a pivotal contributor to PF progression. Finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, has shown potent anti-fibrotic and anti-inflammatory effects in cardiorenal diseases, yet its role in peritoneal fibrosis remains incompletely understood. This study aimed to investigate whether Finerenone alleviates PF by regulating autophagy activity in peritoneal mesothelial cells.

A mouse model of peritoneal fibrosis was established by daily intraperitoneal injection of 4.25% glucose-based peritoneal dialysis solution for 28 days. Finerenone (10 mg/kg) was administered orally concomitantly with dialysis fluid for 28 days. In vitro, human peritoneal mesothelial cells (HPMCs) were stimulated with TGF-β1 (2 ng/mL, 36 h) to induce fibrotic transformation. Cellular morphology, collagen deposition (Masson staining), and fibrosis markers (α-SMA, Fibronectin, Collagen I, and E-cadherin) were assessed by immunohistochemistry, immunofluorescence, and Western blot. Autophagy activity was evaluated by LC3-II/LC3-I ratio, p62 degradation, Beclin-1 and Atg5 expression, and chloroquine (CQ) co-treatment. Finally, Atg5 was silenced using siRNA to confirm its role in Finerenone-induced autophagy.

Finerenone markedly attenuated peritoneal thickening and collagen accumulation in vivo and suppressed TGF-β1-induced fibrotic phenotype in HPMCs. Finerenone decreased α-SMA, Fibronectin, and Collagen I expression while restoring E-cadherin levels. Mechanistically, Finerenone reversed TGF-β1-induced autophagy blockade, as evidenced by increased LC3-II/LC3-I and Beclin-1, upregulated Atg5, and decreased p62 accumulation, indicating enhanced autophagic flux. The autophagy inhibitor CQ abolished these protective effects, leading to LC3-II and p62 accumulation. Moreover, Atg5 knockdown counteracted Finerenone-mediated suppression of fibrosis-related proteins, confirming that Finerenone's anti-fibrotic effects depend on Atg5-mediated autophagy activation. Finerenone also reduced pro-inflammatory cytokines (TGF-β1, IL-6, and IL-1β), suggesting that autophagy restoration alleviates inflammation in parallel.

Finerenone alleviates peritoneal fibrosis, at least in part, by restoring Atg5-mediated autophagic flux and suppressing inflammation in peritoneal mesothelial cells. These findings provide mechanistic insight into its antifibrotic effects and support autophagy modulation as a potential therapeutic strategy for peritoneal dialysis-associated complications.