Organelle synergy unleashed: Modulating mitochondrial-endoplasmic reticulum contacts with a self-assembled prodrug amplifies ferroptosis for innovative cancer therapy

Mitochondrial-endoplasmic reticulum contacts (MERC), a crucial mediator in subcellular organelle communication, significantly influences the dynamics of tumor organelle. Despite the well-established correlation between MERC-associated enzymes and lipid peroxidation (LPO), the contribution of MERC to LPO-induced ferroptosis in tumor remains unclear. In this study, we unveil the role of MERC in amplifying ferroptosis within tumor cells by introducing a prodrug LSA (LA-SS-ART, Linoleic acid-disulfide bond-artesunate), which ingeniously utilizes fatty acids as MERC inducers and ferroptosis activators. LSA induces Vdac-Ip3r-mediated MERC, resulting in the influx of Ca2+ from ER into mitochondria. Consequently, mitochondrial dysfunction triggers lipid peroxidation, attributed to hindered β-oxidation. Furthermore, LSA upregulates the expression of Lpcat3 and Mfn2, promoting phospholipid synthesis and enhancing the production of polyunsaturated fatty acid-phospholipids, synergistically intensifying ferroptosis. In conclusion, this study leverages organelle interactions to finely modulate cellular metabolism and membrane function, ultimately amplifying the process of ferroptosis. These findings offer a perspective and direction for innovative cancer therapy.