Pumping Iron: Ferritinophagy Promotes Survival and Therapy Resistance in Pancreatic Cancer

Abstract

Autophagy is an adaptive response to metabolic and therapeutic stress, especially in treatment-refractory cancers such as pancreatic cancer. In this issue of Cancer Discovery, two groups establish ferritinophagy, a selective autophagy program that could become a drug target, as the mechanism that pumps iron into mitochondria via the lysosome, enabling survival and therapy resistance in pancreas cancer. See related article by Santana-Codina et al., p. 2180 (3). See related article by Ravichandran et al., p. 2198 (4).

Figure 1.

Ferritinophagy drives survival and resistance in pancreas cancer. Ferritinophagy is increased in pancreas cancer. TFEB, a master transcription factor, drives a specific iron metabolism program in addition to lysosomal biogenesis and autophagy. The autophagy cargo receptor NCOA4 binds ferritin, which stores ferric iron (Fe³⁺). NCOA4–ferritin is processed by the autophagy pathway to release bioactive ferrous iron (Fe²⁺) in autolysosomes. The ferritinophagy-dependent excess of cellular iron in PDAC increases iron–sulfur cluster (ISC) protein levels in the mitochondria, enhancing the electron transport chain (ETC), oxidative phosphorylation (OXPHOS), and mitochondrial health, thereby supporting pancreatic cancer growth. MAPK pathway inhibition in PDAC leads to reduced MYC competition for TFEB binding sites on CLEAR promoter elements, enabling induction of ferritinophagy, lysosomal biogenesis, and autophagy genes.