Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis

Abstract

Ferroptosis is a recently-defined tumor suppression mechanism, but the sensitivity of many tumorigenic cells to ferroptosis is limited by their deficient expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Here, we report the discovery of a photosensitizer, namely TPCI, which can evoke ACSL4-independent ferroptosis of cancer cells in photodynamic therapy. Through co-localization with 12-lipoxygenase (ALOX12) in multiple subcellular organelles, TPCI activates ALOX12 to generate lipid reactive oxygen species in large quantity and trigger cell ferroptosis. Intriguingly, confining TPCI exclusively in lysosomes switches the cell death from ferroptosis to apoptosis. More strikingly, the ferroptosis mediated by TPCI-induced ALOX12 activation does not require the participation of ACSL4. Therefore, our study identifies TPCI as the first ALOX12 activator to induce ferroptosis independent of ACSL4, which renders a viable therapeutic approach on the basis of distinct ferroptosis of cancer cells, regardless their ACSL4 expressions.

A review on ferroptosis and photodynamic therapy synergism: Enhancing anticancer treatment

“…Many of them are metal complex, such as iridium (III), Pt (II) and Ru (II) complex [ 37 , [42] , [43] , [44] , [45] ]. But there were also other types of novel photosensitizers that can induce ferroptosis [ [46] , [47] , [48] ]. Boronic acid-derived salicylidenehydrazone (BASHY) dyes were found to be able to induce ferroptosis in human glioblastoma multiform U87 cell line, and BASHY dyes accumulated in lipid droplets, which enhanced photodynamic reaction and the induction of ferroptosis [ 49 ].…”

Ferroptosis in immunostimulation and immunosuppression

“…Thus, the lipid flippase SLC47A1 on the cell membrane may serve as a metabolic checkpoint influencing the induction of various ferroptosis pathways. It is worth noting that ACSL4‐independent ferroptosis has been reported in certain cases, such as photodynamic therapy in human HeLa cancer cells 37 . In addition, ACSL3‐dependent monounsaturated fatty acid (MUFA) production completely inhibits PUFA‐dependent ferroptosis in HT1080 cells, 38 suggesting that different lipid species may have antagonistic effects.…”

The mechanism of ferroptosis and its related diseases

“…Additionally, the S47 variant of TP53, which has been shown to ablate ferroptosis in cells and mice, also results in iron accumulation in macrophages, altering macrophage cytokine profiles and causing increased susceptibility to bacterial infection and limitation of malarial infection. A recent study found that ALOX12 activation induced by a photosensitizer in cancer cells significantly increases lipid reactive oxygen species and promotes ferroptosis, independent of ACSL4 [ 213 ].…”