Carnosic acid protects against ferroptosis in PC12 cells exposed to erastin through activation of Nrf2 pathway

Aims: Ferroptosis is involved in the pathogenesis of spinal cord injury (SCI). Carnosic acid (CA) is a natural phenolic diterpene, which possesses diversiform activities. However, whether the protective effect of CA on SCI is partly due to inhibition of ferroptosis was seldom investigated. Therefore, the objective of this study aimed to investigate the role of CA on ferroptosis in PC12 cells and the underlying mechanisms. Main methods: Cell viability, malondialdehyde (MDA) contents, glutathione (GSH) levels, and iron levels were detected to identify the construction of ferroptosis model in PC12 cell induced by erastin. The safe concentrations of CA on PC12 cells were measured via cell counting kit-8 (CCK-8) assays. Then, cellular MDA contents, GSH levels, iron levels, reactive species (RS) generation, and mitochondrial morphology were tested to determine the influence of CA on ferroptosis in erastin-treated PC12 cells. In addition, Western blot and RT-qPCR were utilized to detecteddetect the ferroptosis-related genes and proteins expression levels. Key findings: Our study indicated that treatment with CA could reversed the increased MDA, iron, and RS levels, as well as the decreased GSH levels in erastin-treated PC12 cells. The protective effect of CA could be blocked by ML385. The inhibitory effect of CA on ferroptosis probably was partially governed by activation of Nrf2 to regulate the GSH synthesis and metabolism and cellular iron homeostasis. Significance: CA can inhibit ferroptosis in PC12 cells induced by erastin via activating Nrf2 pathway, indicating that CA could lead to neuroprotective effect by restraining the occurrence of ferroptosis.