Fresh Dendrobium Officinale Polysaccharides Combine with Penicillamine to Attenuate Copper Overload-Induced Liver Injury in a Rat Model of Wilson’s Disease Via Activation of the Nrf2/HO-1/Keap1 Signaling Pathway

Wilson’s disease (WD) is characterized by pathological copper accumulation, which drives hepatocellular oxidative stress and subsequent liver injury. While the first-line chelator penicillamine (PCA) effectively eliminates copper, it is associated with significant side effects. Dendrobium officinale polysaccharides, the active components in Dendrobium officinale , exhibit significant antioxidant and hepatoprotective effects. However, their potential in ameliorating liver injury in WD and as an adjunctive therapy to PCA remains unclear. This study investigated the hepatoprotective effects and underlying mechanisms of fresh Dendrobium officinale polysaccharides (FDOP), both alone and combined with PCA, in a copper-overloaded rat model. The results showed that FDOP significantly mitigated hepatic histopathological damage and reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (AKP). It also alleviated oxidative stress by decreasing hepatic malondialdehyde (MDA) and oxidized glutathione (GSSG) levels while enhancing superoxide dismutase (SOD) activity. Furthermore, FDOP promoted copper excretion and reduced copper deposition in the liver, brain, and kidneys. Mechanistically, FDOP activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/Kelch-like ECH-associated protein 1 (Keap1) signaling pathway, evidenced by upregulated nuclear Nrf2 and HO-1 expression and downregulated Keap1 expression, thereby enhancing the cellular antioxidant defense system. Importantly, the combination of FDOP and PCA outperformed either monotherapy in alleviating liver injury, promoting copper excretion, and activating antioxidant pathways. In conclusion, FDOP not only exhibits excellent hepatoprotective effects but also holds potential as an adjunct to PCA therapy, offering a novel combined treatment strategy for WD.