Metabolic reprogramming of peritoneal mesothelial cells in peritoneal dialysis–associated fibrosis: therapeutic targets and strategies

Peritoneal dialysis (PD) is considered a life-saving treatment for end-stage renal disease. However, prolonged PD use can lead to the development of peritoneal fibrosis (PF), diminishing its efficacy. Peritoneal mesothelial cells (PMCs) are key initiators of PF when they become damaged. Exposure to high glucose‑based peritoneal dialysis fluids (PDFs) contributes to PF development by directly affecting highly metabolically active PMCs. Recent research indicates that PMCs undergo metabolic reprogramming when exposed to high-glucose PDFs, including enhanced glycolysis, impaired oxidative phosphorylation, abnormal lipid metabolism, and mitochondrial dysfunction. Although this metabolic transition temporarily compensates for the cellular damage and maintains energy levels, its long-term impact on peritoneal tissue is concerning. Multiple studies have identified a close association between this shift in energy metabolism and PF, and may promote the progression of PF through various molecular mechanisms. This review explores recent findings regarding the role and mechanism of PMC metabolic reprogramming in PF progression. Moreover, it provides a summary of potential therapeutic strategies aimed at various metabolic processes, including glucose metabolism, lipid metabolism, and mitochondrial function. The review establishes that targeting metabolic reprogramming in PMCs may be a novel strategy for preventing and treating PD-associated fibrosis. Overview of the metabolic reprogramming of PMCs in PF associated with PD and therapeutic implications. Under physiological conditions, PMCs primarily produce ATP through OXPHOS and FAO to maintain cellular functions. High-glucose PDFs can induce metabolic reprogramming of PMCs, characterized by increased glycolysis, the polyol pathway, and the PPP, inhibited OXPHOS, impaired FAO, lipid exocytosis and deposition, and mitochondrial dysfunction. These metabolic changes lead to peritoneal damage and fibrosis through multiple metabolic pathways. Potential therapeutic strategies target glucose absorption, glycolysis, the polyol pathway, FAO restoration, lipid deposition, and mitochondrial dysfunction. FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; PD, peritoneal dialysis, PDF, peritoneal dialysis fluid; PMC, peritoneal mesothelial cell; PPP, pentose phosphate pathway.