BACKGROUND: Cadmium is known to disrupt cellular proliferation through unregulated cell division. This process leads to activation of TNF-α cytokines, resulting in cellular damage and increased inflammation in cells, including brain cells. This study investigates the regulation of TNF-α and ERK gene expression patterns mediated by N-acetylcysteine in response to cadmium exposure in Wistar rats.‎. METHODS AND RESULTS: Wistar rats (n = 37) were divided into five groups: control (G1), acute cadmium exposure (G2), chronic cadmium exposure (G3), acute cadmium with N-acetylcysteine (G4), and chronic cadmium with N-acetylcysteine (G5). Brain tissue sections were prepared and stained with H&E. Then, the G-FAP was measured ‎using immunohistochemistry. ELISA was employed to detect IL-1β and IL-10 levels. TNF and ERK gene expression ‎was assessed using RT-PCR. Histopathological examination revealed increased glial inflammatory cells in groups G2 and G3. N-acetylcysteine reduced inflammatory cell infiltration, and G-FAP staining confirmed decreased astrocytic accumulation in G5. IL-1β levels significantly decreased in G5 after N-acetylcysteine therapy, while IL-10 levels increased after treatment but subsequently declined due to chronic cadmium exposure. TNF gene expression increased in G2 and G3 but decreased significantly in G5, demonstrating N-acetylcysteine's suppressive effect. Furthermore, ERK gene expression significantly increased in G2 and ‎G3. However, there were notable decreases in both G4 and G5 compared to cadmium-exposed controls. CONCLUSION: This study demonstrated that N-acetylcysteine mitigates oxidative stress-induced tissue damage, prevents apoptosis, and exhibits anti-inflammatory properties by downregulating TNF-α and upregulating ERK gene expression.