Malformin A1-mediated cytotoxicity in ovarian cancer cells occurs through pyroptosis and autophagy.

Cytoskeletal proteins play a crucial role in providing mechanical support and regulating key cellular processes such as cell proliferation, migration, and invasion. Cytoskeletal damage has been increasingly regarded as a contributing factor in impairing these cellular processes in cancer. Moreover, induction of cell death pathways has been linked to cytoskeletal destabilization. However, the effect of cytoskeletal disruption on cell death mechanisms in ovarian cancer (OC) remains elusive. Several natural compounds have been demonstrated to initiate cytoskeletal destabilization as a mechanism to promote cell death. We have previously shown that one such natural compound derived from marine sources, Malformin A1 (MA1), exhibits high toxicity toward both cisplatin-sensitive (A2780S) and cisplatin-resistant (A2780CP) OC cell lines. Thus, here we evaluate the impact of cytoskeletal destabilization by MA1 treatment on OC cell death by analyzing the expression levels of apoptosis, autophagy, and DNA damage-related genes. Our findings show MA1 treatment significantly downregulated key cytoskeletal proteins while also decreasing the expression of pro-apoptotic markers, suggesting alternative cell death mechanisms. Autophagy-related analyses demonstrated enhanced LC3BI to LC3BII processing, indicating autophagy activation with elevated γ-H2AX levels confirming substantial DNA damage in MA1-treated cells. Notably, MA1 was able to induce pyroptotic cell death, as evidenced by increased caspase-1 expression. Moreover, molecular docking analysis revealed that MA1 displayed the strongest binding affinity for vimentin, GAPDH, and β-tubulin, providing mechanistic insights into its ability to disrupt cytoskeletal integrity and induce nonapoptotic cell death through multiple pathways, highlighting MA1's potential as a promising therapeutic candidate.