Flavonoid-mediated modulation of ferroptosis: therapeutic potential in gastrointestinal cancers

The incidence of early-onset gastrointestinal cancer in individuals under 50 has been rising at an alarming rate in recent years. A major challenge in standard therapeutic interventions is the ability of cancer cells to evade apoptosis, which leads to chemoresistance and promotes cancer progression and metastasis. As a result, non-apoptotic forms of cell death, such as ferroptosis, have gained considerable attention as potential therapeutic interventions. Ferroptosis is a unique cell death characterized by iron-dependent lipid peroxidation and regulated through multiple signaling pathways. Cancer cells rely more on iron and are more sensitive to ferroptosis than normal cells. Recently, interest has surged in using natural compounds, particularly flavonoids, as anticancer agents. Flavonoids are increasingly recognized as potent inducers of ferroptosis, offering new therapeutic strategies in cancer therapy.

This review provides a detailed overview of current preclinical evidence on the therapeutic potential of flavonoids that induce ferroptosis in gastrointestinal cancers. First, the general mechanisms of ferroptosis are described, followed by an overview of synthetic compounds or small-molecule modulators. Then, flavonoids are introduced and described in terms of their classification, chemical structure, and anticancer activity. Finally, the gaps, challenges, and future scope of research are addressed.

Flavonoid modulators of ferroptosis target GPX4, the system Xc^-, lipid metabolism, and iron metabolism pathways, in addition to various other pathways, to initiate the cell death process and inhibit carcinogenesis. We hypothesize that flavonoid-induced ferroptosis presents a strategic intervention in cancer therapy, serving as both anticancer agents and sensitizers to enhance the efficacy of current treatments.