Targeting lipid peroxidation-associated ferroptosis suppresses lung carcinoma progression by regulating cell cycle arrest

Lung carcinoma is a frequently encountered cancerous growth that affects the respiratory tract and has a high occurrence rate globally. In LIGHT of the ongoing worldwide health emergency, the significance of efficient therapeutic agents and strategies is of utmost importance. A meticulous control of the cell cycle is crucial for comprehending the pathophysiology and molecular causes of lung Cancer, as well as for the formulation of efficacious therapeutic medicines. The mechanism by which cells synchronize cell cycle with cell survival and death is still not fully understood. In this study, we demonstrate that the halting of the cell cycle has a strong inhibitory impact on Ferroptosis, a specific type of controlled cell death triggered by excessive lipid peroxidation at the membranes of cells. Ferroptosis is halted through the mechanism of cell cycle arrest, which involves the deposition of intracellular lipids mediated by diacylglycerol Acyltransferase (DGAT). Excessive amounts of polyunsaturated fatty acids (PUFAs) are stored as triacylglycerols (TAGs) within inactive cells. As a result, inhibiting DGAT causes a rearrangement of PUFAs from TAGs to Phospholipids and makes arrested cells more susceptible to Ferroptosis. We demonstrate that certain lung Cancer cells that are resistant to antimitotic drugs and have a slow-cycling behavior exhibit an increase in lipid droplets. Furthermore, we find that the growth of tumors resistant to 5-fluorouracil, lorlatinib, and docetaxel can be effectively suppressed by a combination treatment involving the use of Ferroptosis inducers and DGAT inhibitors, which induces Ferroptosis. Collectively, these findings demonstrate the involvement of cell cycle arrest in conferring resistance to Ferroptosis and propose a potential therapeutic approach for addressing the challenge of slow-cycling malignancies that exhibit resistance to Ferroptosis.

Cell cycle; Chemotherapy; Drug resistance of lung cancer; Ferroptosis; Lung cancer.