RTA-408 overcomes cisplatin-resistant lung cancer by inhibiting WWP1-mediated NCOA4 ubiquitination to induce ferritinophagy and ferroptosis.

Worldwide, pulmonary carcinoma remains the predominant cause of cancer-induced fatalities. Cisplatin (DDP) is a platinum-containing cell cycle-non-specific chemotherapeutic agent and serves as the first-line treatment for non-small cell lung cancer (NSCLC). However, NSCLC cells gradually develop resistance to cisplatin during treatment, reducing drug sensitivity and leading to a significant decrease in the effect of chemotherapy or even treatment failure. The main mechanisms of drug resistance include reduced cellular uptake and apoptotic escape. Strategies to reverse drug resistance often suffer from off-target toxicity or inconsistent efficacy, highlighting the urgent need for new drugs that specifically target resistance pathways. Accordingly, we screened a library of small-molecule compounds associated with ferroptosis. We identified 4-7D (also known as RTA-408), a nuclear factor erythroid 2-related factor 2 activator initially developed to treat Friedreich's ataxia, which has shown potent anti-NSCLC activity in preclinical studies. Its unique ability to regulate both oxidative stress and apoptotic pathways makes it a promising candidate for overcoming cisplatin resistance. Therefore, the present study aimed to determine the key role of omaveloxolone (RTA-408) in overcoming cisplatin-resistant lung cancer. We selected A549/DDP cells as a research model and demonstrated through a series of experimental manipulations that RTA-408 inhibited the growth of A549/DDP cells and inhibited the ubiquitinated degradation of nuclear receptor coactivator 4 through down-regulation of WW structural domain-containing E3 ubiquitin-protein ligase 1 (WWP1), which further induced the development of ferritinophagy and ferroptosis. We report for the first time that RTA-408 overcomes cisplatin-resistant lung cancer by targeting WWP1-mediated ferritinophagy and ferroptosis.