Melittin induces ferroptosis and ER stress-CHOP-mediated apoptosis in A549 cells

Abstract

Melittin is a natural polypeptide present in bee venom, with significant anti-tumor activity. Melittin has been reported to induce cell death in lung carcinoma cell line A549 cells, suggesting an excellent potential for treating lung cancer. However, the core mechanism underlying melittin-induced cell death in A549 cells remains unclear. This work reports that melittin induces reactive oxygen species (ROS) burst, upregulates intracellular Fe²⁺ levels, disrupts the glutathione-glutathione peroxidase 4 antioxidant system, and increases lipid peroxide accumulation, eventually inducing cell death, indicating that ferroptosis may be involved in the antitumor effects of melittin in A549 cells. Furthermore, A549 cells treated with the ferroptosis inhibitors ferrostatin-1 and deferoxamine demonstrated that these inhibitors could reverse the cell death induced by melittin, further confirming that melittin induces A549 cell death via ferroptosis. Furthermore, the results also illustrated that melittin activated the endoplasmic reticulum (ER) stress-CHOP (C/EBP homologous protein) apoptotic signal, closely associated with high-level intracellular ROS. The ER stress inhibitor, 4-Phenylbutyric acid, was used to confirm that ER stress-CHOP apoptotic signaling is another molecular mechanism of melittin-induced A549 cell death. Thus, our results demonstrate that ferroptosis and ER stress-CHOP signaling are key molecular mechanisms of melittin-induced cell death in lung cancer.

KEY POLICY HIGHLIGHTS

• Melittin upregulates intracellular Fe²⁺ levels, leading to the accumulation of lipid peroxides in A549 cells.

• Melittin disrupts the glutathione-glutathione peroxidase 4 antioxidant system in A549 cells.

• Melittin induces activation of endoplasmic reticulum stress-C/EBP homologous protein apoptosis signal.

• Ferroptosis and ER stress are the core molecular mechanisms underlying melittin-induced cell death in A549 cells.

Graphical Abstract

Keywords:

• Melittin
• A549 cells
• reactive oxygen species (ROS)
• Ferroptosis
• ER stress

Acknowledgements

The authors are grateful to the Core Facility of the School of Life Sciences, Lanzhou University.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data used to support the findings of this study are available from the corresponding author upon request.

Additional information

Funding

This work was supported by the Life Oasis Public Service Center, Qujiang District, Quzhou City under Grant BJHA-CRP-004.