BACKGROUND: The development of aseptic necrosis of the femoral head is accompanied by complex disturbances of the molecular and cellular regulation of bone metabolism. Existing conservative treatment options are not always effective, and surgical techniques are not directly aimed at inhibiting bone destruction. Thus, investigating alterations in intercellular interactions in the development of aseptic necrosis offers the prospect of introducing targeted therapy to normalize bone remodeling signaling. AIM: To study the protein profile of cancellous bone from the proximal femoral epiphysis in the development of aseptic necrosis in an experimental animal model. METHODS: We analyzed the protein profile of cancellous bone samples from the proximal femoral epiphysis in Wistar rats after surgical induction of aseptic necrosis and in healthy control animals. Proteomic profiling was performed using high-performance liquid chromatography with mass spectrometry on both the aseptic necrosis side and the healthy contralateral side. Proteins were identified using FragPipe software with MSFragger, IonQuant, and Philosopher modules on the Windows 11 operating system with preinstalled Java and AMD64 architecture. Protein identification was considered reliable with a false discovery rate of less than 1% and the presence of at least two unique peptides. The rat protein database (Rattus norvegicus) SwissProt and the common Repository of Adventitious Proteins (cRAP) contaminant database were used for analysis. RESULTS: A total of 1288 proteins were isolated in 12 samples, of which 989 were common to both control and aseptic necrosis samples, 114 were found only in control samples, and 82 only in aseptic necrosis samples. Gene Ontology cellular component analysis showed that proteasomes accounted for the largest number of associated proteins. By biological function, these included proteins involved in coagulopathy, fibrinolysis, glycolysis, gluconeogenesis, catabolic processes, and cellular response to interleukins 7, 1, 4, and 6; by molecular function, these included NAD-binding proteins, ADP-binding proteins, antigen-interacting proteins, and P-type calcium transporter proteins. Bioinformatic analysis of the protein profile revealed the importance of uncontrolled inflammatory responses and endothelial dysfunction in the breakdown of compensatory mechanisms in the development of aseptic necrosis of the femoral head. CONCLUSION: Analysis of signaling pathway interaction networks in the development of aseptic necrosis confirmed the role of endothelial dysfunction and dysregulation of compensatory mechanisms at the molecular and cellular level. Moreover, the development of uncontrolled inflammation may play a leading role in progressive bone destruction.