Huaier Sensitizes Oxaliplatin-Resistant Colorectal Cancer to Oxaliplatin by Reducing P-Glycoprotein and Inducing Nrf2/SLC7A11/GPX4-Dependent Ferroptosis.

BACKGROUND: Chemoresistance to oxaliplatin (OXA) in colorectal cancer (CRC) remains a major cause of treatment failure. This study investigated whether Huaier polysaccharide (HP) could reverse OXA resistance and explored the underlying mechanisms.

METHODS: Cell viability and proliferation were assessed using the Cell Counting Kit-8 (CCK-8) assay and colony formation assays, respectively. Protein expression was analyzed by Western blotting. Ferroptosis was evaluated using a lipid peroxidation probe (BDP 581/591 C11), FerroOrange, a reactive oxygen species (ROS) assay kit, and a total glutathione detection kit. Ultrastructural changes were observed using transmission electron microscopy. Nuclear and cytoplasmic protein extraction and immunofluorescence were used to examine nuclear factor erythroid 2-related factor 2 (Nrf2) expression.

RESULTS: Combined treatment with OXA and HP significantly suppressed cell viability and proliferation by inhibiting the Nrf2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) pathway, thereby inducing ferroptosis. In addition, HP reduced P-glycoprotein expression and enhanced sensitivity to OXA.

CONCLUSIONS: These findings demonstrate that Huaier overcomes OXA resistance in CRC cells by promoting ferroptosis through suppression of the Nrf2/SLC7A11/GPX4 signaling pathway in vitro.