Abstract

Background Non-small cell lung cancer (NSCLC) remains a significant health challenge, and the KRAS mutation plays a critical role in its development, especially KRAS G12C . Rosmarinic acid (RA), a natural polyphenolic compound, has demonstrated robust anti-cancer activities. However, the precise molecular mechanisms underlying its anti-tumor effects in NSCLC remain poorly understood. Methods We assessed RA’s anti-tumor effects in in vitro/in vivo NSCLC models. Activity-based protein profiling (ABPP) coupled with bioorthogonal click chemistry identified RA’s direct molecular targets. Western blot and other techniques analyzed KRAS/AKT/ERK signaling, plus cell cycle/apoptosis molecule expression. The effect of RA on tumor suppression and the ability of tumor cells to evade macrophages in an NSCLC mouse model with KRAS G12C mutation was evaluated. Results RA significantly inhibited NSCLC cell proliferation and induced apoptosis by modulating the KRAS/AKT/ERK signaling cascade. ABPP analysis revealed that RA directly binds to KRAS G12C at the mutant cysteine-12 residue. Functional studies confirmed that RA-mediated cell cycle arrest and apoptosis depend on KRAS G12C modulation. In KRAS G12C -mutant mouse models, RA markedly suppressed tumor growth and reduced macrophage evasion by tumor cells. Conclusions RA acts as a novel KRAS G12C inhibitor that directly targets the mutant cysteine-12 residue, suppressing NSCLC progression through inhibition of the KRAS/AKT/ERK pathway and enhancement of anti-tumor immune activity. These findings highlight RA’s therapeutic potential for KRAS G12C -driven NSCLC and offer new insights for the development of targeted cancer therapies.