HMGB1 secretion by resveratrol in NSCLC: A pathway to ferroptosis-mediated platelet activation suppression

Background: Cancer-associated venous thromboembolism (CAT) is a frequent and serious complication in cancer patients. Resveratrol, a natural compound with reported anti-tumor effects, is not fully understood in its role regarding CAT in lung cancer. This study aims to explore resveratrol's potential to diminish platelet activation induced by lung adenocarcinoma cells and uncover the underlying mechanisms. Methods: Clinical data on coagulation function in non-small cell lung cancer (NSCLC) patients were gathered. A549 human lung cancer cells and Lewis mouse lung cancer cells were employed to assess tumor-induced platelet activation and the impact of resveratrol on this process. Western blotting analyzed protein expression, electron microscopy examined extracellular vesicle (EV) morphology, flow cytometry measured platelet activation, reactive oxygen species (ROS), and exocrine protein expression, while ELISA quantified secretory proteins. Tumor control and platelet function were studied in tumor-bearing mice. Results: We identified that hematological profiles of NSCLC patients frequently manifest a hypercoagulable state relative to healthy controls and lung cancer cells could instigate platelet activation, yet resveratrol could attenuate this phenomenon induced by lung cancer. Resveratrol stimulates lung cancer cells to release HMGB1enriched EVs, promoting platelet ferroptosis and inhibiting platelet activation through increased ROS, lipid peroxidation, and disrupted cystine transporters. In vivo studies confirm that resveratrol inhibits lung cancer cell growth and suppresses tumor-induced platelet activation in mice. Conclusion: Our studies revealed that resveratrol alleviated lung cancer-induced ferroptosis associated platelet activation. This suggests a potential pharmacological approach for preventing and treating both lung cancer and CAT.