Lysosomal dysfunction contributes to lead (Pb) and high-fat diet (HFD)-induced neuronal apoptosis: A link with cathepsin B
- Neurotoxicology. 2026 May:114:103462. doi: 10.1016/j.neuro.2026.103462.
- 1. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
- 2. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
- 3. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
- 4. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
- 5. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
- 6. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
- 7. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
- 8. State Key Laboratory of Microbial Technology, Qingdao, Shandong 266000, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250100, China; Institute of Marine Science and Technology, Shandong University, Qingdao, Shandong 266000, China. Electronic address: [email protected].
- 9. Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong 250100, China; Institute of Marine Science and Technology, Shandong University, Qingdao, Shandong 266000, China. Electronic address: [email protected].
- 10. Zhengzhou Center for Disease Control and Prevention, Zhengzhou, Henan 450052, China. Electronic address: [email protected].
- 11. Department of Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, Henan province 450001, China. Electronic address: [email protected].
Environmental lead (Pb) exposure and high-fat diet (HFD) intake are known to trigger massive neuronal Apoptosis that contributes to neurologic dysfunction. Previous studies mainly focused on isolated mitochondrial dysfunction, autophagy-lysosomal pathway damage, and neuronal Apoptosis from Pb or HFD. Nevertheless, the precise role of the lysosomal and proteasomal clearance processes in promoting neuronal cell death induced by Pb and HFD remains unclear. In this study, male Sprague-Dawley (SD) rats were employed to elucidate the mechanisms underlying Pb-induced neurotoxic mitochondrial Apoptosis and to investigate the effects of co-exposure to HFD. In vitro, PC12 cells were treated with Pb and palmitic acid (PA) to mimic the in vivo conditions. Specifically, such exposures prompted the translocation of Cathepsin B (CTSB) from lysosomes to the cytosol and downregulation of lysosomal-associated membrane protein 1 (LAMP1), ATPase H⁺ Transporting V1 Subunit A (ATP6V1A), and Bcl-2 within rat cortex. In contrast, the levels of pro-apoptotic factors including BID, Bax, mitochondrial cytochrome C (Cyt C), and Caspase 3 were significantly elevated. We also observed a significant decrease in the fluorescence intensity of lysosomes while lysosomal pH was ascertained to have ascended appreciably. Concurrently, CTSB inhibition by CA-074 me prevented neural Apoptosis processing triggered by Pb and/or PA via mitigating lysosomal damage and mitochondrial Cyt C translocation, indicating that CTSB is a key mediator in the apoptotic process induced by Pb and HFD.