S-adenosylmethionine inhibits non-small cell lung cancer and enhances chemosensitivity by targeting the P62/NF-κB axis and regulating autophagy and oxidative stress

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Despite advances in targeted therapies and immunotherapy, which have improved survival rates, drug resistance and immune-related side effects continue to necessitate the development of new treatments. S-adenosylmethionine (SAM), a key metabolite in the methionine cycle, has indicated potential for cancer therapy and enhancing chemotherapy sensitivity. However, its effects on NSCLC remain undetermined. In our study, SAM inhibits NSCLC growth and enhances chemosensitivity both in vitro and in vivo. Mechanistic investigations revealed that SAM plays a significant regulatory role in autophagy and oxidative stress within NSCLC. Furthermore, we identified P62 as a critical target of SAM by constructing biotin-labeled SAM for immunocoprecipitation-mass spectrometry. Both in vitro and in vivo studies confirmed that P62 mediates SAM regulatory effects on NSCLC. Furthermore, by constructing truncated P62 expression plasmids for immunocoprecipitation experiments, we discovered that SAM inhibits the NF-κB signaling pathway by directly targeting the ZZ and TB domains of the P62 protein, thereby blocking autophagy and activating oxidative stress. These findings highlight SAM as a novel inhibitor of the P62/NF-κB axis and suggest that SAM could be a potential therapeutic agent for NSCLC.