The Effect and Molecular Mechanism of Fto Gene Knockout on Cadmium-Induced Injury in Pancreatic β-Cells

Cadmium exposure results in the impairment of pancreatic β-cells. The FTO protein, the product of the Fto gene, is a key regulator of diverse pathophysiological processes, including oxidative damage and cell death. However, it remains unclear whether Fto gene knockout affects cadmium-induced pancreatic β-cell damage, and the precise mechanisms involved are yet to be elucidated. Under conditions of cadmium exposure, Fto gene knockout was found to alleviate pancreatic β-cell damage significantly. Specifically, Fto gene knockout counteracted cadmium-induced cytotoxicity-manifested as reduced cell viability, increased apoptosis, and heightened lactate dehydrogenase (LDH) release-while simultaneously suppressing DNA damage and preserving cellular membrane integrity. On a molecular level, Fto gene knockout markedly mitigated cadmium-induced oxidative stress. This was achieved by curbing excessive reactive oxygen species (ROS) accumulation, lowering malondialdehyde (MDA) generation, and reducing 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, alongside restoring superoxide dismutase (SOD) activity. Furthermore, ER-Tracker Red staining revealed that cadmium treatment induced clustered aggregation of the endoplasmic reticulum (ER) and increased fluorescence intensity, suggesting the activation of endoplasmic reticulum stress (ERS). Conversely, Fto knockout ameliorated ER morphological abnormalities, thereby effectively antagonizing the excessive activation of ERS. In summary, our study elucidates the impact and underlying molecular mechanisms of the Fto gene in cadmium-induced toxicity in pancreatic β-cells from the perspectives of oxidative damage, ERS, and apoptosis. These findings identify the Fto gene as a potential molecular target for mitigating cadmium-induced toxicity in pancreatic β-cells, thereby providing a new theoretical basis for the prevention and treatment of cadmium-induced pancreatic β-cell injury.