A novel fluorescent probe for visualizing viscosity changes in lipid droplets during chemotherapy-induced ferroptosis

Background: Ferroptosis, as a novel form of cell death, is becoming one of the hot topics in cancer treatment research. It differs from necrosis and autophagy in that it involves the accumulation of lipid peroxides and is triggered by iron dependency. Recent studies have suggested that this mechanism may alter the viscosity or structure of lipid droplets (LDs). The relationship between LDs viscosity and ferroptosis remains an active area of research with limited reports at present. Additionally, there is a lack of effective anticancer drugs targeting the ferroptosis pathway to promote ferroptosis in tumour cells. Therefore, the development of tools to detect viscosity changes during ferroptosis and targeted therapeutic strategies is of great significance. Results: By coupling 1,3-indandione with naphthalimide, including decamethylamine as a LDs recognition group, we designed and synthesized an environmental fluorescent probe that induces intramolecular charge transfer (TICT) effects. Notably, the diffusion and transport of intracellular substances may be affected in highly viscous environments. Under such conditions, intracellular iron ions may accumulate, leading to peroxide production and cellular damage, which can trigger ferroptosis. Therefore, WD -1 achieved excellent in situ bioimaging of LDs targeting and its viscosity during ferroptosis in HeLa cells and zebrafish. Furthermore, it was observed that WD -1 effectively differentiated between malignant and normal cells during this process, highlighting its potential significance in distinguishing cellular states. In addition, we used the antitumour drug paclitaxel to study ferroptosis in cancer cells. These findings not only provide an excellent tool for the development of the ferroptosis response, but also are crucial for understanding the biological properties of LDs during the ferroptosis response. Significance and novelty: Based on a powerful tool of fluorescent probe with in vivo bioimaging, we developed WD1 to track the impact of paclitaxel on the process of ferroptosis in living cells. Therefore, we preliminarily believe that paclitaxel may affect the occurrence of ferroptosis and control apoptosis in cancer cells. These findings not only serve as an exceptional tool for advancing our understanding of the ferroptosis response, but furthermore play a vital role in comprehending the biological characteristics of LDs in relation to ferroptosis.