Modulation of the PI3K/Akt signaling pathway by steroidal saponins: therapeutic implications in cancer

Abstract

Background The phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway is considered essential for cancer progression and the regulation of cellular processes, including proliferation, survival, metastasis, and angiogenesis. Conventional therapies using targeted agents such as alpelisib and everolimus have limited the effectiveness of inhibitors in exploiting effective resistance mechanisms. Steroidal saponins (SSs) are a diverse group of natural compounds recognized as anticancer agents that target multiple cells and pathways.Purpose To synthesize current evidence on how SSs modulate the PI3K/Akt pathway to produce anticancer effects and to outline translational opportunities and limitations.Methods We conducted a review of preclinical and translational studies indexed in PubMed/Scopus/Google Scholar up to August 2025. Studies were included if they reported mechanistic or functional modulation of the PI3K/Akt/mTOR axis (in vitro, in vivo, or ex vivo). Relevant data were compiled and organized based on compound class, experimental model, dose/exposure, and PI3K/Akt-related molecular readouts.Results and Discussion This review highlights the potential of SSs to target the PI3K/Akt pathway and combat cancer progression, and addresses the limitations of conventional therapies in overcoming therapeutic resistance. SSs, as small-molecule phytochemicals, exert anticancer effects through the induction of apoptosis, inhibition of metastasis and angiogenesis, alteration of the tumor microenvironment to therapeutic advantage, promotion of the immune response, and other mechanisms that reverse multidrug resistance by modulating the PI3K/Akt pathway.Conclusion The combination of SSs with chemotherapeutic agents, given emerging preclinical evidence of small-molecule efficacy, supports the development of new anticancer therapies. However, the development of SSs for clinical use remains limited due to their low bioavailability, systemic toxicity, and lack of target specificity.