Mollugin induces ferroptosis through dysregulation of iron homeostasis and redox balance in non-small cell lung cancer

Background: Lung Cancer remains one of the most prevalent and lethal malignancies worldwide, with non-small cell lung Cancer (NSCLC) constituting the predominant subtype, necessitating the development of effective therapeutic strategies. Although mollugin (MOL) has shown Anticancer potential, its specific efficacy and mechanism of action against NSCLC remain unclear.

Purpose: This study aimed to systematically investigate the anti-NSCLC activity of MOL and to elucidate the underlying molecular mechanisms.

Study design: The study combined in vitro experiments using NSCLC cell lines and in vivo efficacy evaluation in a mouse xenograft model.

Methods: The effects of MOL on NSCLC cell proliferation, migration, mitochondrial function, and redox homeostasis were assessed. The role of NCOA4-mediated ferritinophagy and Keap1/Nrf2/GPX4 axis was examined using pharmacological inhibitors and NCOA4 knockdown.

Results: MOL significantly inhibited NSCLC cell proliferation, suppressed cell migration, induced mitochondrial dysfunction, and disrupted redox homeostasis. Mechanistically, MOL induced Ferroptosis by activating NCOA4-mediated ferritinophagy and modulating the Keap1/Nrf2/GPX4 signaling pathway. This ferroptotic effect was abrogated by NCOA4 knockdown and the Keap1 inhibitor KI696. MOL also showed an enhancing effect on the efficacy of paclitaxel. In vivo, both low and high doses of MOL effectively inhibited lung tumor growth without causing significant systemic toxicity.

Conclusion: This study identifies MOL as a novel ferroptosis-inducing agent against NSCLC, acting through dual-pathway modulation of ferritinophagy and the Keap1/Nrf2/GPX4 axis. These findings highlight the potential of MOL as a promising therapeutic candidate for NSCLC treatment.