Tissue & cell · 2025
Phosphocreatine alleviates liver fibrosis in diabetic mice by targeting TGF-β/Smad and α-SMA pathways.
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Wang Fu Han, Qaed Eskandar, Aldahmash Waleed, Mahyoub Mueataz A, Al-Mutairi Dalal Sanad, Tang Zeyao, Almoiliqy Marwan
Аннотация
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.
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.