Rosmarinic acid inhibits non-small cell lung cancer progression by directly targeting KRASG12C and modulating the KRAS/AKT/ERK signaling axis.

BACKGROUND

Non-small cell lung cancer (NSCLC) remains a significant health challenge, and the KRAS mutation plays a critical role in its development, especially KRASG12C. 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 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 KRASG12C 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 KRASG12C at the mutant cysteine-12 residue. Functional studies confirmed that RA-mediated cell cycle arrest and apoptosis depend on KRASG12C modulation. In KRASG12C-mutant mouse models, RA markedly suppressed tumor growth and reduced macrophage evasion by tumor cells.

CONCLUSIONS

RA acts as a novel KRASG12C 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 KRASG12C-driven NSCLC and offer new insights for the development of targeted cancer therapies.