Phosphocreatine alleviates liver fibrosis in diabetic mice by targeting TGF-β/Smad and α-SMA pathways.

PURPOSE: This study aimed to investigate the protective effects of phosphocreatine (PCr) on diabetes-induced liver fibrosis and to explore the underlying mechanisms, particularly its impact on the TGF-β/Smad signaling pathway.

METHODS

A diabetic liver fibrosis model was established in mice using streptozotocin and carbon tetrachloride (CCl₄). Mice were treated with PCr, and liver tissues were analyzed using histological staining (H&E, Masson), ELISA, Western blot, and high-resolution respirometry (HRR) to assess fibrosis, inflammation, oxidative stress, and mitochondrial function. Protein levels of TGF-β, Smad2/3, α-SMA, and collagen type I were quantified to evaluate HSC activation.

RESULTS

PCr significantly reduced collagen deposition and restored liver architecture. It attenuated oxidative stress, as evidenced by lower Malondialdehyde (MDA) levels and higher Superoxide Dismutase SOD activity, reduced pro-inflammatory cytokines including TNF-α and IL-6, improved liver function as shown by decreased ALT and AST levels, and enhanced mitochondrial respiration. Mechanistically, PCr downregulated TGF-β, phosphorylated Smad2/3, α-SMA, and collagen type I, indicating suppression of HSC activation.

CONCLUSION

PCr alleviates liver fibrosis in diabetic mice by inhibiting the TGF-β/Smad pathway and improving mitochondrial function, suggesting its potential as a therapeutic agent for diabetic liver fibrosis.