Baicalin modulates endoplasmic reticulum-Golgi homeostasis via targeting ATF6-GBF1 axis to alleviate copper-induced...

Copper (Cu) exposure caused by environmental contamination or dietary imbalance poses a potential threat to poultry health by inducing renal dysfunction and disrupting cellular homeostasis. Baicalin (BA), a natural flavonoid with antioxidant and anti-inflammatory properties, has shown renoprotective potential. However, whether and how BA alleviates Cu-induced nephrotoxicity remains unclear. Disruption of endoplasmic reticulum (ER)-Golgi trafficking impairs cellular homeostasis and may contribute to renal injury, but its role in Cu-induced kidney damage has not been fully defined. In this study, using duck in vivo and in vitro Cu exposure models, we found that Cu downregulated the Golgi structural protein GBF1 and disrupted ER-Golgi trafficking, leading to Golgi fragmentation, ER swelling, and ER stress activation via ATF6. Functional assays revealed that GBF1 knockdown further decreased the expression of Golgi structural and trafficking-related proteins and exacerbated ER stress, whereas ATF6 silencing partially reversed these molecular alterations. Moreover, our results provide evidence that BA can stably bind to ATF6, inhibit its activation and proteolytic cleavage, restore the expression of Golgi and trafficking-related proteins, and reduce ER stress, thereby maintaining organelle homeostasis. In summary, our results identify the GBF1-ATF6 axis as a key pathway in Cu-induced ER-Golgi dysregulation and nephrotoxicity, and provide mechanistic insight into the protective role of BA in restoring subcellular homeostasis.