Potassium Sorbate Triggers Kidney Injury via Dysregulated Intercellular Communication: A Study Combining Network Toxicology, Machine Learning, Molecular Docking, and Single‐Cell RNA Sequencing

ABSTRACT Acute kidney injury (AKI) is a clinically significant syndrome, characterized by high mortality rates and the potential for progression to chronic kidney disease. Potassium sorbate (PS), a widely‐used food preservative with a high safety profile, has been identified as a potential risk factor for inducing acute kidney injury. However, the mechanism of its potential nephrotoxicity, particularly in relation to the onset of AKI, remains unclear. This study provides a comprehensive examination of the molecular mechanisms of PS‐induced kidney injury, employing a variety of methodologies including network toxicology, molecular docking, molecular dynamics simulation, machine learning, and single‐cell analysis. The findings suggest that PS interacts with key targets such as matrix metallopeptidase 9 (MMP9) and amyloid precursor protein (APP), affecting lipid metabolism and atherosclerosis, as well as AGE‐RAGE signaling pathways. These interactions trigger oxidative stress, inflammatory responses, and metabolic disorders, thereby facilitating the development of acute kidney injury. Machine learning screening identified the APP as a key regulatory gene. Furthermore, single‐cell analysis revealed that APP, via APP‐CD74 and APP‐PTGER2 ligand–receptor pairs, mediates interactions between endothelial cells and immune cells. This provides novel cellular evidence for understanding PS‐induced kidney tubular inflammation and microenvironmental imbalance. This study not only offers systematic scientific evidence for evaluating the nephrotoxicity of PS, but also introduces an innovative research paradigm that integrates multiple dimensions for the safety assessment of food additives and the exploration of the molecular mechanisms of acute kidney injury.