Abstract
Matrine and its derivatives, as multi-target natural alkaloids, exhibit synergistic antitumor effects through the regulation of core oncogenic pathways including Wnt/β-catenin, MAPK/ERK, and PI3K/AKT/mTOR. These compounds inhibit tumor proliferation by suppressing epithelial-mesenchymal transition (EMT), inducing programmed cell death (apoptosis, autophagy, and pyroptosis), and remodeling the tumor immune microenvironment. Preclinical studies demonstrate that third-generation derivatives (e.g.MT-26, YF-18) enhance therapeutic efficacy by targeting DNMT1/HDAC6 dual inhibition and activating the NLRP3/caspase-1 pyroptosis pathway, achieving tumor suppression rates of 60-78% in pancreatic and liver cancer patient-derived xenograft (PDX) models while overcoming chemotherapy resistance. However, preclinical-to-clinical translation faces challenges such as low bioavailability, off-target toxicity (e.g.hepatotoxicity via JNK/c-Jun activation), and tumor heterogeneity-driven resistance mechanisms (eg SLC7A11-mediated ferroptosis evasion); notably, no Phase I/II clinical trials for matrine or its derivatives in cancer therapy have been registered to date. Future research should prioritize the development of intelligent delivery systems (DNA origami nanorobots, magnetically guided micro/nano-swimmers), multi-omics-driven precision strategies (spatial metabolomics, single-cell epi-drugomics), and synthetic biology platforms (PROTAC bifunctional molecules, AI-assisted crystal screening). Integrating organ-on-chip technologies and real-world data analytics will accelerate the transformation of matrine-based compounds into next-generation intelligent anticancer agents, offering innovative solutions for comprehensive cancer management.