Hederacolchiside A1 targets ERO1A to suppress PI3K/AKT/mTOR signaling and induce ferroptosis in colorectal cancer.

Abstract

Colorectal cancer (CRC) remains a major global health challenge due to high incidence, poor prognosis, and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising anti-tumor strategy, yet pharmacological inducers remain underexplored. Hederacolchiside A1 (HeA1), a natural bioactive compound, was investigated for its potential anti-CRC effects and underlying mechanisms. In vitro, HeA1 inhibited proliferation, migration, and invasion of HT-29, SW-480, HCT-116, and MC-38 cells in a dose-dependent manner, induced apoptosis, and modulated epithelial-mesenchymal transition (EMT) markers, increasing E-cadherin and decreasing Vimentin, Slug, MMP2, and MMP9. Ferroptosis induction was evidenced by increased reactive oxygen species (ROS), lipid peroxidation, and intracellular Fe2+, along with a decrease in reduced glutathione (GSH) and a concomitant increase in oxidized glutathione (GSSG). HeA1 directly targeted endoplasmic reticulum oxidoreductase 1 alpha (ERO1A), resulting in suppression of PI3K/AKT/mTOR signaling and downregulation of ferroptosis defense proteins SLC7A11 and GPX4. In HT-29 xenograft models, HeA1 significantly reduced tumor volume and weight, decreased Ki67 and CD31 expression, increased TUNEL-positive cells, and exhibited minimal systemic toxicity. Immunofluorescence and Western blot analyses confirmed inhibition of PI3K/AKT/mTOR pathway components and ferroptosis-related proteins in vivo. Collectively, these findings demonstrate that HeA1 exerts potent anti-CRC effects by directly targeting ERO1A to induce ferroptosis through inhibition of the PI3K/AKT/mTOR-SLC7A11/GPX4 axis. This study provides a mechanistic rationale for further development of HeA1 as a potential therapeutic agent for colorectal cancer.