Identification of Pinostilbene as a natural STING agonist that triggers FTH1 degradation via K48-ubiquitination to induce ferroptosis in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) treatment faces significant challenges due to drug resistance and toxicity. Emerging evidence suggests that ferroptosis, an iron-dependent form of regulated cell death, is a promising therapeutic strategy. We identify Pinostilbene, a natural stilbenoid, as a potent and novel STING agonist. Our findings reveal that Pinostilbene effectively activates the STING/TBK1/IRF3 pathway, leading to the transcriptional upregulation of downstream cytokines. Importantly, we demonstrate that Pinostilbene significantly enhances the sensitivity of lung cancer cells to RSL3-induced ferroptosis. Mechanistically, Pinostilbene promotes the degradation of the iron-storage protein Ferritin Heavy Chain 1 (FTH1), a key negative regulator of ferroptosis. We uncover a novel mechanism in which Pinostilbene induces FTH1 degradation through the ubiquitin-proteasome system via K48-linked polyubiquitination, a process independent of NCOA4-mediated ferritinophagy. This FTH1 degradation increases the labile iron pool, a critical prerequisite for ferroptosis. In vivo, Pinostilbene exhibits robust antitumor efficacy alone and achieves synergistic tumor growth inhibition when combined with RSL3 in a NSCLC mouse model without systemic toxicity. Its therapeutic effect is linked to STING activation and FTH1 downregulation, which coincides with an increase in the ferroptosis biomarker 4-HNE. Furthermore, Pinostilbene enhances antitumor immunity by upregulating inflammatory cytokines and promoting the infiltration and activation of tumor-killing CD8⁺ T cells, alongside drving anti-tumor M1 polarization of macrophages. Our study highlights the potential of Pinostilbene as a promising therapeutic agent for NSCLC, offering a multifaceted mechanism of action through ferroptosis sensitization and immunostimulation.