Lithium chloride induces mitophagy and suppresses proliferation in endometrial cancer spheroids by promoting intermediate filament accumulation

Lithium chloride (LiCl), a mood stabilizer and GSK-3β inhibitor, has been suggested to modulate cellular stress responses and exert antitumor effects. This study investigates the impact of LiCl treatment on mitophagy and intermediate filament (IF) accumulation in endometrial cancer spheroids derived from Ishikawa cells. Cell viability, proliferation, and colony-forming ability were assessed following exposure to various concentrations of LiCl (1, 10, and 50 mM). Ultrastructural analyses revealed mitochondrial degradation and IF aggregation, indicative of mitophagy, particularly at higher LiCl doses. Ultrastructural analyses demonstrated the presence of isolation membranes encircling mitochondria in nearly all LiCl-treated spheroids, indicating widespread mitophagy. In addition to these mitophagic features, high LiCl doses were associated with cytoplasmic intermediate filament accumulation and lytic cytoplasmic changes, suggesting a dose-dependent cytoskeletal response to mitochondrial stress. IF accumulation co-occurred with mitophagic features, suggesting a potential yet unexplored interplay between intermediate filaments and mitophagy in cancer spheroids. These findings provide new insights into the role of cytoskeletal stress in cancer progression and chemoresistance.