CNNM4: a ferroptotic vulnerability in cholangiocarcinoma

Abstract

Cholangiocarcinoma (CCA) represents one of the most aggressive malignancies affecting the biliary tree, with limited treatment options and high mortality rates. Despite recent advances in molecular oncology, the prognosis for CCA remains poor, highlighting the urgent need for novel therapeutic strategies. In this context, the study published by Mercado-Gomez et al ,1 provides significant insights into the role of CNNM4, a magnesium transporter, as a regulator of ferroptosis in CCA. By demonstrating how CNNM4 influences magnesium homoeostasis, oxidative stress and cancer metabolism, this study lays the groundwork for exploring targeted therapies aimed at modulating ferroptosis as an anticancer approach (figure 1). Figure 1 Targeting CNNM4 to induce ferroptosis and reduce tumour aggressiveness in cholangiocarcinoma (CCA). This schematic illustrates how CNNM4 inhibition via siRNA reshapes CCA biology, shifting tumour cells from a proliferative and resistant state to one that is more vulnerable to cell death. On the left, CCA cells exhibit high CNNM4 expression, actively transporting magnesium (Mg²+) out of the cell, a process that supports tumour survival, metabolic adaptation and therapy resistance. On siRNA-mediated CNNM4 silencing (centre), this balance is disrupted, leading to intracellular iron (Fe) accumulation and triggering ferroptosis, an iron-dependent form of programmed cell death that CCA cells normally evade. On the right, CNNM4 inhibition results in a profound shift in tumour behaviour—reducing drug resistance, altering metabolic pathways, decreasing cancer stem cell properties and ultimately suppressing metastasis. On the bottom, the mechanisms that link magnesium accumulation and induction of ferroptosis are indicated. These findings highlight CNNM4 as a promising therapeutic target, where its inhibition not only promotes ferroptosis but also weakens CCA’s most aggressive traits, opening new avenues for treatment (Created with BioRender). ROS, reactive oxygen species. Magnesium is …