Unusual Iron-Independent Ferroptosis-like Cell Death Induced by Photoactivation of a Typical Iridium Complex for Hypoxia Photodynamic Therapy

Ferroptosis is a unique cell death mode that relies on iron and lipid peroxidation (LPO) and is extensively utilized to treat drug-resistant tumor. However, like the other antitumor model, requirement of oxygen limited its application in treating the malignant tumors in anaerobic environments, just as photodynamic therapy, a very promising anticancer therapy. Here, we show that an iridium(III) complex (Ir-dF), which was often used in proton-coupled electron transport (PCET) process, can induce efficient cell death upon photo irradiation, which can be effectively protected by the typical ferroptosis inhibitor Fer-1 but not by the classic iron chelating agents and ROS scavengers. Surprisingly, LPO was further demonstrated to be directly induced by Ir-dF/light activation via PCET, by utilizing a model polyunsaturated fatty acid. Ir-dF was found to be accumulated preferentially in mitochondria and the endoplasmic reticulum (ER), leading to mitochondrial swelling and ER stress accompanied by obvious LPO accumulation and downregulation of the characteristic ferroptosis protein GPX4. More interestingly, Ir-dF was also found to induce photocytotoxicity under hypoxia, and an in vivo experiment further confirmed that Ir-dF can effectively inhibit the growth of tumor under two-photon laser irradiation. Taken together, for the first time, this article introduces a new mechanism of inducing the LPO through a photoactivated PCET process, leading to a ferroptosis-like cell death which is independent of the iron and oxygen. This innovative mechanism holds great potential as a future treatment option for hypoxic malignant tumors and drug-resistant tumors.