FOLFIRINOX Combined with GPX4 Inhibition Induces Ferroptosis and Defines Redox-Based Therapeutic Subgroups in Pancreatic Cancer

PurposeFerroptosis is a regulated form of cell death with therapeutic relevance in pancreatic ductal adenocarcinoma where Redox accumulation contributes to chemoresistance and poor prognosis. In this study, we aimed to evaluate the efficacy of combining the FOLFIRINOX regimen with a GPX4 inhibitor, RSL3, and to identify Redox-related predictive and prognosis biomarkers. Experimental DesignA combination of in vitro and in vivo models were used to evaluate oxidative stress, apoptosis, ferroptosis, and the modulation of Redox proteins, GPX4 and SOD2. Furthermore, survival analyses were assessed with a 122 retrospective human pancreatic cancer cohort. ResultsThe novel GPX4 inhibitor, RSL3, enhanced the effect of FOLFIRINOX by inducing ROS accumulation that triggered ferroptosis and apoptosis in vitro and a significant tumor shrinkage in vivo in those high ROS levels tumor cells. In contrast, SOD2 overexpression conferred resistance. Furthermore, high GPX4 and ROS expression levels were associated with shorter survival, while elevated SOD2 levels showed a subgroup with better prognosis in our cohort of 122 human pancreatic cancer cases. Thus, a novel molecular signature based on a GPX4-high/SOD2-low profile may help detect patients with the poorest clinical outcomes in pancreatic cancer. ConclusionsRedox homeostasis regulates susceptibility to ferroptosis and influences treatment efficacy in pancreatic ductal adenocarcinoma. Notably, sensitivity to ferroptosis was determined not only by GPX4 levels alone, but also by the balance between ROS accumulation and SOD2-mediated antioxidant buffering. These findings support a biomarker-guided approach to treatment stratification and provide a rationale for the clinical evaluation of redox-based therapeutic strategies in pancreatic ductal adenocarcinoma. Translational relevanceFerroptosis is a non-apoptotic form of cell death with emerging therapeutic potential in pancreatic ductal adenocarcinoma. This study demonstrates that combining FOLFIRINOX with the GPX4 inhibitor RSL3 selectively induces ferroptosis in tumors with high ROS levels, both in vitro and in vivo, without increasing toxicity. Notably, sensitivity to ferroptosis is not determined by GPX4 levels alone, but rather by the tumors capacity to tolerate oxidative stress, shaped by ROS accumulation and compensatory SOD2 expression. In our clinical cohort, high GPX4 and elevated ROS levels correlate with poor prognosis, whereas high SOD2 expression identifies a favorable subgroup. These findings establish redox signaling as a clinically relevant variable for defining novel molecular subtypes with prognostic significance and support the use of redox biomarkers for patient stratification in pancreatic ductal adenocarcinoma. This work provides a strong rationale for the clinical evaluation of ferroptosis-inducing agents in combination with standard chemotherapy in phase I trials, guided by tumor redox profiling to enhance therapeutic precision.