ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies and systematic chemotherapies are the most commonly-used standard treatment for PDAC patients diagonosed at advanced stages. However, drug resistance may arise as early as several weeks after chemotherapy initiation, thus limiting the therapeutic efficacy of chemotherapy reagents. Accumulating evidence has demonstrated that acquired tolerance to apoptotic cell death induced by cytotoxic drugs is one of the critical reasons for the failure of chemotherapy. Ferroptosis was originally identified as a unique form of programmed cell death, which is characterized by shrunk mitochondria accompanied with condensed membranes and decreased crista, in drug screens searching for small molecules that can selectively kill RAS-expressing cancer cells. Unlike apoptosis, ferroptosis is driven by iron-catalyzed excessive lipid peroxidation, ultimately leading to the rupture of plasma membrane and cell death. Recent studies indicated that ferroptosis induction can be a promising therapeutic strategy in cancer treatment since it not only can kill tumor cells directly but also can synergize with chemotherapy ,radiotherapy,targeted therapy and immunotherapy. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. Therefore, unravelling the underlying mechanisms responsible for reduced sensitivity to ferroptosis inducers, such as erastin or RSL3, may pave the way for designing effective therapeutic regimens for PDAC patients.
