Ferroptosis, autophagy, and mitochondrial dynamics: Front burners in cancer therapeutics

This article comments on the article by Rana and Prajapati published in the recent issue. Cancer remains the most formidable public health problem and contributes to significant mortality worldwide. Tumor heterogeneity, toxicity and acquired resistance limit the efficacy of widely used cancer therapies such as radiotherapy, chemotherapy, gene therapy, and immunotherapy. Regulated cell death maintains cellular homeostasis and is a primary hallmark of cancer. Review by Rana and Prajapati discusses the mechanistic regulation of ferroptosis, autophagy, and mitochondrial dynamics in cancer and highlights the therapeutic possibilities of these regulated cell death pathways for developing more effective and targeted cancer therapies, mainly for aggressive and drug-resistant tumors. Considering the important regulatory role of ferroptosis, autophagy and its dynamic interplay with mitochondrial metabolism in tumor pathogenesis, therapy resistance and metastasis, reshaping of the tumor microenvironment with modulations in autophagy and mitochondrial function could sensitize ferroptosis-resistant tumors to anticancer drugs thereby increase the therapeutic efficacy of existing treatment regimens. Deeper understanding of the crosstalk may lead to the identification of non-invasive biomarkers for detecting ferroptosis-sensitive and resistant tumors, prediction of treatment response and the development of clinically translatable pharmacological strategies to maximize patient benefit while minimizing adverse outcomes.