Nutrient stress-induced FTH1 safeguards redox balance and fuels pancreatic ductal adenocarcinoma growth while serving as a therapeutic target and diagnostic biomarker

Nutrient-poor tumor microenvironments drive metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) cells; however, how iron homeostasis is remodeled under nutrient stress and how this influences tumor fate remains unclear. Here, we show that low-glucose conditions markedly increase free, bioavailable iron levels in PDAC cells, likely due to impaired iron-sulfur cluster assembly and enhanced heme degradation by upregulated heme oxygenase-1 (HMOX1). Concomitantly, nutrient stress activates the AMPK-NRF2-FTH1 axis; induced FTH1 sequesters excess iron, preserves redox balance and fuels proliferative capacity. FTH1 is markedly elevated in human PDAC tissues, and high expression is associated with poor survival. In a collected PDAC serum cohort, ferritin levels were found to be elevated in at least 71% of cases. In vivo, a high-iron diet combined with FTH1 inhibition arrests tumor growth, establishing FTH1 as a tractable therapeutic target. Functionally, the proliferative impact of FTH1 loss depends on tumor cell nutritional status; exogenous metabolic substrates such as pyruvate and fructose fully rescue proliferation defects caused by FTH1 depletion. Furthermore, across metabolic interventions, the tumor proliferation rate inversely correlates with FTH1 abundance. An analysis of paired serum samples from pancreatic cancer patients revealed that gemcitabine-based first-line therapy elicits a marked increase in circulating FTH1 protein, underscoring its potential as a real-time indicator of therapeutic efficacy. Collectively, FTH1 orchestrates iron rewiring and redox homeostasis under nutrient stress within the tumor microenvironment, driving PDAC progression and offering dual clinical value as both a target and a therapeutic-response indicator.