Matrine Suppresses Lung Cancer Progression via Dual Inhibition of CHEK1-Mediated DNA Damage Repair and PI3K/AKT Survival Signaling.

Lung cancer remains a leading cause of cancer-related mortality worldwide, necessitating the development of novel therapeutic strategies. Matrine, a natural alkaloid derived from Sophora flavescens, has demonstrated broad antitumor properties, yet its underlying mechanisms, particularly concerning DNA damage response, remain incompletely elucidated. This study integrates network pharmacology, bioinformatics, and experimental validation to uncover a novel dual-targeting mechanism of matrine in lung cancer. Bioinformatics analysis identified CHEK1 as a key potential target. In vitro, matrine selectively inhibited proliferation, migration, invasion, and clonogenic survival of A549 and LLC cells, while reducing the G2/M phase proportion, indicating G2/M checkpoint impairment. Mechanistically, matrine concurrently downregulated CHEK1, p-PI3K, p-AKT, BCL-2, and EMT markers (Vimentin, MMP2, MMP9), and upregulated γH2AX, E-cadherin, Bax, and Cleaved Caspase-3. Crucially, siRNA experiments revealed that PI3K knockdown induced apoptosis without affecting CHEK1/γH2AX, whereas CHEK1 silencing promoted apoptosis independently of PI3K/AKT, demonstrating complementary. In vivo, matrine significantly inhibited LLC tumor growth in a xenograft model, suppressed proliferation (Ki67), and modulated the CHEK1-PI3K/AKT axis, corroborated by IHC and Western blotting. Importantly, matrine exhibited no significant systemic toxicity. Our findings unveil that matrine exerts potent antitumor effects by simultaneously inhibiting CHEK1-mediated DNA repair and PI3K/AKT survival signaling, presenting a novel dual-targeting approach for lung cancer treatment.