Translating the Crosstalk Between Unfolded Protein Response and Ferroptosis to Cancer Therapies

To survive the proteotoxic and oxidative stress that are prototypical of rapidly multiplying cells, cancer cells must successfully navigate two existential threats: the danger of protein misfolding in the endoplasmic reticulum and the peril of iron-catalyzed peroxidation of membrane lipids. Over the past few decades, the cellular responses to these pressures have been studied independently. This review underscores emerging evidence coupling two erstwhile distinct cellular processes: (i) the unfolded protein response (UPR) that acts as a guardian of proteostasis and a crucial metabolic rheostat, through its three arms (IRE1α, PERK, and ATF6) and (ii) ferroptosis that leads to cell death due to iron-dependent accumulation of lethal levels of lipid peroxides. Multiple intersections between UPR and ferroptosis control the fate of cells, with a well-compensated UPR response leading to cell survival whereas an overwhelmed UPR response routing cells to ferroptosis, depending on cellular contexts such as the expression of antioxidant enzymes, the composition of membrane lipids, and the bioavailability of catalytic iron. The crosstalk has been shown to occur at different hierarchical levels, from shared upstream stress signals to convergent signaling cascades and downstream transcriptional networks. Preclinical drug-response profiles and mechanistic studies provide compelling evidence that combining UPR modulation with ferroptosis induction may represent viable cancer therapies. Investigation of the molecular determinants and context dependence of the UPR-ferroptosis axis will be critical for developing rational combination strategies toward clinical translation.