Uterine leiomyosarcoma (Ut‑LMS) is a rare and aggressive malignant tumor with limited therapeutic options. Therefore, exploration of novel treatment strategies is necessary. MG132 is a potent proteasome inhibitor that has shown promising potential in cancer therapy by inducing apoptosis through disruption of protein homeostasis. Despite its promising applications in various cancers, its effects on Ut‑LMS remains largely unexplored. Therefore, the present study investigated the effects of MG132 on Ut‑LMS cell lines (SK‑LMS‑1, SK‑UT‑1 and SK‑UT‑1B) in terms of cytotoxicity, apoptosis induction, cell cycle progression, autophagy and reactive oxygen species (ROS) production. Treatment with MG132 (0‑2 µM for 24 h) induced a dose‑dependent reduction in cell viability across all three cell lines, and the lactate dehydrogenase release assays confirmed membrane damage. Moreover, apoptosis induction was assessed using annexin V and 7‑AAD staining, which revealed dose‑dependent apoptosis in all three cell lines. Western blot analysis revealed increased cleaved poly‑adenosine diphosphate ribose polymerase and caspase‑3 levels, thereby indicating activation of the apoptotic pathway in response to MG132 treatment. MG132 also induced G₂/M phase arrest in SK‑LMS‑1 and SK‑UT‑1 cells and altered the expression of cell cycle regulatory proteins, such as p21, p27 and p53. Furthermore, MG132 promoted autophagy in all three cell lines by increasing light chain 3 II levels. ROS levels remained unchanged in SK‑LMS‑1 cells but increased in SK‑UT‑1B and SK‑UT‑1 cells. Furthermore, the ROS scavenger N‑acetylcysteine effectively reduced MG132‑induced apoptosis in SK‑UT‑1 cells. These findings highlight the cytotoxicity of MG132 in Ut‑LMS cells, emphasize its potential as a therapeutic agent for Ut‑LMS, provide insights into its mechanisms of action, and suggest possible strategies for improving treatment efficacy.

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