29 / 2026-03-14 21:29:59

Identifying Epigenetic Vulnerabilities Induced by Dietary Methionine Restriction in Non-Small Cell Lung Cancer (NSCLC)

3D genome organization,epigenetic remodel,dietary manipulation

Lung cancer remains the leading cause of cancer-related deaths worldwide. Among its subtypes, non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is associated with a poor 5-year overall survival rate of 17.4%. Despite advances in NSCLC therapies, clinical outcomes remain limited due to the emergence of resistance to first-line treatments and the absence of targetable alterations in nearly 50% of NSCLC patients. These challenges highlight a critical need to develop new therapeutic strategies that can benefit a broader population of patients with NSCLC. One emerging approach involves dietary manipulation, as diet determines the availability of circulating nutrients and has been shown to directly influence cancer risk and progression. Among these strategies, a methionine-restricted (MR) diet has shown notable potential due to the elevated methionine dependency of NSCLC cells. However, actionable epigenetic therapeutic dependencies remain elusive.



To address this, we conducted high-throughput epigenetic drug screening in combination with multi-omics analyses. Our results demonstrate that MR suppresses the growth of NSCLC cells and induces G2/M cell-cycle arrest regardless of mutation status, accompanied by a global reduction in histone methylation. Beyond these effects, MR drives widespread epigenomic reorganization and sensitizes NSCLC cells to specific epigenetic inhibitors. Further validation indicates that this epigenomic reorganization underlies the increased sensitivity to these inhibitors. Collectively, our findings reveal that MR induces novel druggable vulnerabilities in NSCLC and provide a foundation for future mechanistic studies and evaluation of combination therapeutic strategies.