Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Rosmarinic acid inhibits non-small cell lung cancer progression by directly targeting KRASG12C and modulating the KRAS/AKT/ERK signaling axis.
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Zhao Wentong, Zhang Qian, He Yujing, Xing Xuefeng, An Yehai, Zhang Ying, Li Wenhui, Yang Shiguang, Xiong Xuan, He Weiyi, Wong Yin-Kwan, Yang Shilin, Rao Shuan, Feng Yulin, Luo Piao, Wang Jigang
Аннотация
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.
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.