Keywords
PI3K/AKT/mTOR
MAPK
Ferroptosis
Autophagy
PD-L1
Combination therapy
Submitted : 2025-09-17
Accepted : 2025-10-02
Published : 2025-10-17
Abstract
Plant-derived alkaloids exhibit significant anticancer potential, yet their multi-target mechanisms, spanning signaling pathways, programmed cell death, immunity, and metabolism, remain fragmented. This narrative review synthesizes recent preclinical evidence on five representative alkaloids: dendrobine (DDB), aloperine (ALO), levo-tetrahydropalmatine (L-THP), solamargine (SM), and cyclovirobuxine D (CVB-D). Using a dual-framework of compound-specific analysis and key regulatory modules (NF-κB, MAPK, PI3K/AKT/mTOR, JAK/STAT; apoptosis, autophagy, ferroptosis; immune checkpoints; metabolism/microbiota), the study identified convergent anticancer mechanisms with translational relevance. These alkaloids consistently suppress NF-κB, PI3K/AKT/mTOR, and MAPK pathways, and modulate JAK/STAT signaling. They induce apoptosis and ferroptosis, and block autophagic flux. Notably, EVO and SM downregulate PD-L1 via the MUC1-C/NF-κB/c-MYC axis, enhancing CD8⁺ T cell function. L-THP activates AMPK and remodels tumor metabolism. These mechanistic insights support rational co-therapies such as L-THP plus metabolic inhibitors, or ALO combined with bispecific immune checkpoint inhibitors. Overall, these alkaloids demonstrate systemic, multi-pathway anticancer efficacy, and represent promising partners in precision combination therapy. Clinical translation should prioritize formulation and pharmacokinetic optimization, biomarker-guided stratification, and preclinical validation of synergistic regimens.
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