Abrine targets ERK to suppress EMT and lung metastasis model via MAPKs and Nrf2/Keap-1/HO-1 signaling.

Abrine, an indole alkaloid, was evaluated for its anti-metastatic activity and mechanism in non-small cell lung cancer (NSCLC) models. Human A549 and H1975 cells were exposed to Abrine, showing no cytotoxicity but marked suppression of TGF-β1-induced migration and invasion by scratch and Transwell assays. Mechanistically, Abrine reversed epithelial-mesenchymal transition (EMT) by upregulating E-cadherin and reducing N-cadherin, vimentin, Snail and Slug, findings corroborated by immunofluorescence. Abrine also diminished phosphorylation of ERK, JNK and p38 while modulating the Nrf2/Keap-1/HO-1 axis. Target engagement was supported by molecular docking, CETSA, DARTS, and MST indicating specific binding and thermal stabilization of ERK. In vivo, Abrine (20 or 40 mg/kg) mitigated lung metastasis in a B16-F10 intravenous model, improving body weight, decreasing lung metastatic burden, lung wet weight and lung index, and reducing Ki67 expression in lung tissue. Systemic effects included lowered circulating IL-17, IL-10, TNF-α and IFN-γ, and absence of overt histopathological toxicity in major organs. Combination with the ERK1/2 inhibitor SCH772984 further enhanced efficacy. Collectively, Abrine exerts potent anti-metastatic effects by directly targeting ERK to inhibit MAPK signaling, reversing EMT and engaging the Nrf2/Keap-1/HO-1 pathway, highlighting Abrine alone or with ERK inhibition as a promising therapeutic strategy against lung metastasis model.