Dendrobium officinale inhibits colorectal cancer progression by induction of glutathione peroxidase 4-mediated ferroptosis

Colorectal cancer (CRC), one of the leading causes of cancer-related mortality globally, urgently requires complementary and alternative therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising anti-cancer strategy. Dendrobium officinale (D. officinale), a renowned traditional Chinese medicinal herb, is widely used in several Asian countries for its nutritional and therapeutic benefits. Although D. officinale has demonstrated anti-tumor effects, the molecular mechanisms underlying its action against CRC remain incompletely characterized. This study aimed to elucidate the role of D. officinale in suppressing CRC through the induction of ferroptosis and its regulatory effects on glutathione peroxidase 4 (GPX4), a key suppressor of ferroptosis. In vitro assays were conducted using HCT116 and SW480 CRC cell lines, and in vivo efficacy was evaluated in BALB/c nude mice bearing CRC xenografts. D. officinale significantly reduced CRC cell viability and proliferation in vitro and suppressed tumor growth in vivo. Induction of ferroptosis was evidenced by elevated levels of Fe²⁺, malondialdehyde (MDA), and lipid peroxidation, along with a depleted glutathione/oxidized glutathione disulfide (GSH/GSSG) ratio. Notably, these effects were reversed by ferroptosis inhibitors, including ferrostatin-1 (Fer-1) and deferoxamine. Consistently, D. officinale markedly downregulated GPX4 expression. Overexpression of GPX4 rescued D. officinale-induced ferroptosis, whereas GPX4 silencing exacerbated this effect. D. officinale suppresses CRC by triggering GPX4-dependent ferroptosis, providing a novel, naturally derived therapeutic approach. These findings bridge traditional medicine and modern oncology, establishing a foundation for developing targeted CRC treatments.