This study investigates the impact of cadmium (Cd) exposure on renal cell ferroptosis. Key findings include: 1. **Cd Exposure Causes Renal Damage**: Cd exposure induced acute kidney injury (AKI) in mice, characterized by nuclear consolidation, brush border detachment, elevated serum uric acid (UA), and increased expression of kidney injury molecule 1 (Kim-1). Transcriptomics analyses revealed disruptions in the arachidonic acid (ARA) metabolic pathway. 2. **Lipid Peroxidation and Mitochondrial Damage**: Cd exposure led to increased levels of oxidized ARA metabolites, renal malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE), indicating lipid peroxidation. Mitochondrial lipid peroxidation was confirmed using MitoDePDD and flow cytometry. Mitochondrial membrane rupture and reduced mitochondrial cristae were observed in Cd-exposed kidneys. 3. **Mitochondrial SIRT3 and GPX4 Acetylation**: Cd exposure resulted in downregulation of mitochondrial SIRT3, an NAD+-dependent deacetylase, and elevated acetylation of mitochondrial GPX4, a key antioxidant enzyme. This was confirmed using co-immunoprecipitation and Western blotting. 4. **SIRT3 Knockout Exacerbates Cd-Induced Ferroptosis**: Sirt3 knockout mice showed more severe Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis, as evidenced by increased oxidized lipid metabolites and renal pathology. 5. **NMN Pretreatment Attenuates Cd-Induced Ferroptosis**: Pretreatment with nicotinamide mononucleotide (NMN), a precursor for NAD⁺ synthesis, reduced Cd-induced mitochondrial lipid peroxidation, GPX4 acetylation, and renal cell ferroptosis in both in vitro and in vivo models. These results suggest that mitochondrial GPX4 acetylation, likely due to SIRT3 downregulation, plays a crucial role in Cd-induced renal cell ferroptosis. NMN, by restoring mitochondrial SIRT3 activity, could potentially prevent environmental stress-induced AKI.This study investigates the impact of cadmium (Cd) exposure on renal cell ferroptosis. Key findings include: 1. **Cd Exposure Causes Renal Damage**: Cd exposure induced acute kidney injury (AKI) in mice, characterized by nuclear consolidation, brush border detachment, elevated serum uric acid (UA), and increased expression of kidney injury molecule 1 (Kim-1). Transcriptomics analyses revealed disruptions in the arachidonic acid (ARA) metabolic pathway. 2. **Lipid Peroxidation and Mitochondrial Damage**: Cd exposure led to increased levels of oxidized ARA metabolites, renal malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE), indicating lipid peroxidation. Mitochondrial lipid peroxidation was confirmed using MitoDePDD and flow cytometry. Mitochondrial membrane rupture and reduced mitochondrial cristae were observed in Cd-exposed kidneys. 3. **Mitochondrial SIRT3 and GPX4 Acetylation**: Cd exposure resulted in downregulation of mitochondrial SIRT3, an NAD+-dependent deacetylase, and elevated acetylation of mitochondrial GPX4, a key antioxidant enzyme. This was confirmed using co-immunoprecipitation and Western blotting. 4. **SIRT3 Knockout Exacerbates Cd-Induced Ferroptosis**: Sirt3 knockout mice showed more severe Cd-induced mitochondrial GPX4 acetylation and renal cell ferroptosis, as evidenced by increased oxidized lipid metabolites and renal pathology. 5. **NMN Pretreatment Attenuates Cd-Induced Ferroptosis**: Pretreatment with nicotinamide mononucleotide (NMN), a precursor for NAD⁺ synthesis, reduced Cd-induced mitochondrial lipid peroxidation, GPX4 acetylation, and renal cell ferroptosis in both in vitro and in vivo models. These results suggest that mitochondrial GPX4 acetylation, likely due to SIRT3 downregulation, plays a crucial role in Cd-induced renal cell ferroptosis. NMN, by restoring mitochondrial SIRT3 activity, could potentially prevent environmental stress-induced AKI.