Targeting the HGF/MET axis in cancer: therapeutic promise for natural compounds

The hepatocyte growth factor (HGF)/MET signaling pathway plays a pivotal role in cancer progression, metastasis, and therapeutic resistance, making it an attractive target for anticancer therapies. HGF, a multifunctional cytokine, binds to the MET receptor, triggering downstream pathways such as PI3K/AKT, MAPK/ERK, and STAT3, which regulate cell proliferation, survival, and epithelial-mesenchymal transition (EMT). Dysregulation of this pathway-through mutations, amplifications, or overexpression-contributes to tumorigenesis, drug resistance, and poor prognosis in various cancers, including lung, breast, gastric, and hepatocellular carcinomas. This review explores the molecular mechanisms of HGF/MET in cancer, highlights the therapeutic potential of natural compounds, and discusses ongoing clinical trials targeting this pathway. Despite advances in targeted therapies, resistance to MET inhibitors remains a clinical challenge, necessitating alternative strategies. Natural compounds, including flavonoids, curcumin, ginger derivatives, epigallocatechin-3-gallate (EGCG), honokiol, metformin, and resveratrol, exhibit potent inhibitory effects on the HGF/MET axis. These phytochemicals modulate MET expression, disrupt downstream signaling, and reverse chemoresistance by targeting key oncogenic mechanisms such as EMT, cancer stem cell (CSC) maintenance, and tumor microenvironment interactions. For instance, flavonoids like apigenin and quercetin suppress MET-mediated invasion, while curcumin inhibits PI3K/AKT/mTOR signaling. EGCG and honokiol demonstrate synergistic effects with conventional therapies, overcoming resistance in non-small cell lung cancer (NSCLC) and renal cell carcinoma. By synthesizing preclinical and clinical findings, this work highlights the therapeutic potential of phytochemicals as adjunctive or alternative agents, offering innovative approaches to enhance the efficacy and outcomes of cancer treatments.