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Ferroptosis, an oxidative cell death mechanism, is driven by iron-dependent lipid peroxidation. Despite being generally associated with lipid peroxidation that overwhelms endogenous repair systems, ferroptosis mechanisms and regulators in various pathological contexts remain elusive. Identifying novel modulators of the ferroptosis pathway is essential for cell-death marker development and drug discovery to target this process. Small molecule drugs and dietary intervention of metabolites and lipids can modulate ferroptosis sensitivity in diverse disease contexts. In this thesis, I investigated lipid metabolism involving ferroptosis in cancer models and an infectious lung disease model. I dissected the different roles of PUFA-containing phospholipids in dietary modulation of ferroptosis and discovered a specific phospholipid class, phosphatidylcholine with diacyl-polyunsaturated fatty acid tails (PC-PUFA2; diacyl-PUFA-PC) that promote ferroptosis. Exogenous PC-PUFA2 or free PUFA enriches PC-PUFA2 abundance in cancer cells and accounts for the ferroptosis-sensitizing effects. I also discovered the accumulation of PC-PUFA2 in the mitochondria, which disrupts mitochondrial redox homeostasis and initiates lipid peroxidation in the endoplasmic reticulum. These findings unveil the essential roles of diacyl-PUFA phospholipids during ferroptosis. Utilizing biomarkers of ferroptosis, I studied the pathogenic mechanism of COVID-19-associated pulmonary diseases. Elevated ferroptosis markers including transferrin receptor 1 and lipid peroxidation products were detected in human COVID-19 lung autopsies. Dysregulation in lipid profile, including a significant decrease in PUFA phospholipids and accumulation of lysophospholipids, further suggests dysregulation of lipid metabolism and ferroptosis that may contribute to inflammation and acute lung injury in COVID-19 lungs. Iron metabolism is affected in the COVID-19 lung and is associated with ferroptosis activation. We further discovered a strong correlation of ferroptosis markers with lung injury severity in a COVID-19 model using Syrian hamsters. These findings provide the fundament for targeting ferroptosis as a novel therapeutic and diagnostic strategy for various diseases.