Pathogenesis and novel therapeutic perspectives in non-small cell lung cancer: Focusing on PI3K/AKT pathway regulation by traditional Chinese medicine monomers

Non-small cell lung cancer (NSCLC) remains a leading cause of global cancer mortality, with treatment efficacy limited by drug resistance and tumor heterogeneity. The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway functions as a central “command hub” that integrates diverse oncogenic signals and coordinates downstream processes to drive tumor progression. Active monomers derived from traditional Chinese medicine (TCM) represent a promising therapeutic strategy due to their multi-target regulatory properties, yet a systematic and critical review of their mechanisms and translational potential is warranted. This is a comprehensive narrative review that synthesizes and critically evaluates the current body of literature on the role of the PI3K/AKT pathway in NSCLC pathogenesis and the potential of TCM monomers to modulate this pathway. The pathogenesis of NSCLC involves a dynamic, interconnected network of mechanisms, with PI3K/AKT as a core regulatory hub. TCM monomers modulate this pathway through distinct mechanisms: direct inhibition of core components (e.g., curcumol, fucoxanthin); modulation of upstream receptors (e.g., dictamnine, shikonin); regulation of micro-RNA networks (e.g., anwulignan, icariin); induction of oxidative stress (e.g., plumbagin, berberine); and coordinated regulation of mitochondrial function and epithelial–mesenchymal transition (e.g., vitexin, cardamonin). Substantial preclinical evidence supports their antitumor efficacy. However, clinical translation is consistently hindered by critical gaps, including relatively high effective concentrations in vitro, a near-universal lack of pharmacokinetic data, and undefined direct molecular targets. TCM monomers targeting the PI3K/AKT pathway offer a promising multi-target strategy for NSCLC adjuvant therapy. Future research must prioritize elucidating their direct targets, optimizing pharmacokinetic profiles, and rigorously assessing safety to bridge the translational gap. Development guided by a biomarker-driven precision medicine framework and exploration of rational combinations with conventional therapies are essential to advance these agents towards clinical application.