Ferroptosis, an iron-dependent regulated cell death, is implicated in several diseases, including cancer and neurodegeneration. While most ferroptosis inhibitors act as radical-trapping antioxidants, Show more
Ferroptosis, an iron-dependent regulated cell death, is implicated in several diseases, including cancer and neurodegeneration. While most ferroptosis inhibitors act as radical-trapping antioxidants, direct modulation of pro-ferroptotic enzymes remains underexplored. Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), a key regulator of ferroptosis, has emerged as a promising therapeutic target. Here, we report a fragment-based screening that identified a benzofuran hit (compound 8, IC50 = 33 ÎĽM), leading to the discovery of two selective ACSL4 inhibitors: compound 15b (LIBX-A402, IC50 = 0.33 ÎĽM) and compound 21 (LIBX-A403, IC50 = 0.049 ÎĽM). Compound 21 is the most potent ACSL4 inhibitor reported to date and shows no activity against ACSL3. Molecular modeling and mutagenesis support its binding in the ACSL4 fatty acid pocket. The strong antiferroptotic activity of both compounds in cells, together with confirmed target engagement for 21, underscores the relevance of ACSL4 as a target for ferroptosis modulation. Show less
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical inv Show more
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies. Show less