The research focus of this Doctoral Thesis is to study the following unanswered questions related to NCOA4 and its central role in iron biology under healthy and disease conditions. In Chapter 1 we review the biology of NCOA4, its physiological role and its potential role in neurodegenerative disorders (ND). Many NDs have been associated with inappropriate iron accumulation in areas most susceptible to disease leading to oxidative stress, altered ferritin levels, and abnormal decreases in the autophagy-lysosomal pathway. Chapter 2 investigates the functional role of NCOA4-mediated ferritinophagy in regulating systemic iron homeostasis and the erythroid cell autonomous role of NCOA4 in erythropoiesis. Chapter 3 evaluates the non-autonomous contribution of NCOA4 to erythropoiesis by NCOA4 function in macrophages. Next, in Chapter 4 we studied long-term liver iron overload using mouse models of iron overload to understand the cellular pathways that lead to pathological changes or those that may provide protection against damage. To achieve this, we employ a state-of the art mass spectrometry-based quantitative proteomics approach. Chapter 5 is based on an exciting finding from chapter 4 where we identify a new role for NCOA4-mediated ferritinophagy during long-term iron overload in vivo. In Chapter 6 a new role for ferritinophagy is discovered in pancreatic cancer pathogenesis. Last, the primary tool utilized in the experimental methods supporting this Doctoral Thesis is proteomics, a high-throughput technology. As highlighted in Chapter 7, multi-omics approaches have helped to address important questions regarding the etiology and genetic/molecular background of different cancers at a level not otherwise attainable with conventional methods. However, we reflect on the need to recognize the potential harms of face value interpretation of these high-throughput analyses. Ethical concerns may arise when some of these large-scale omics studies fail to represent the broader population’s genetic diversity, potentially exacerbating cancer health disparities..