Ferroptosis, a type of regulated cell death driven by iron-catalyzed lipid peroxidation of polyunsaturated fatty acids (PUFA) in membrane phospholipids, plays a significant role in metabolic dysfunction-associated steatotic liver disease (MASLD). This review highlights the molecular mechanisms of ferroptosis in liver physiology, evidence of ferroptosis in human MASLD, and the results of ferroptosis targeting in preclinical models. Ferroptosis is implicated in the progression of MASLD, leading to liver fibrosis and hepatocellular carcinoma (HCC). The rewiring of redox, iron, and PUFA metabolism in MASLD creates a proferroptotic environment, contributing to HCC development. Ferroptosis induction may offer a promising approach to eradicate HCC, while its inhibition could alleviate MASH disease progression. Ferroptosis is characterized by the accumulation of lipid hydroperoxides, which can lead to cell death through direct or indirect mechanisms. The key regulators of ferroptosis include glutathione peroxidase 4 (GPX4), which detoxifies lipid hydroperoxides, and the systemXc- antiporter, which maintains glutathione (GSH) levels. Other membrane-residing reductants, such as ubiquinol and tetrahydrobiopterin (BH4), also protect against ferroptosis. Ferroptosis is distinct from apoptosis and other forms of regulated necrosis, as it involves the release of intracellular content and is morphologically and biochemically distinct. In MASLD, ferroptosis is associated with increased levels of oxidative phospholipid products, such as 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), which are markers of lipid peroxidation. Ferroptosis is also linked to the release of danger-associated molecular patterns (DAMPs), such as oxidized phospholipids (oxPL), which can promote inflammation and fibrosis. The gut-liver axis plays a crucial role in MASLD, with intestinal dysbiosis and gut-derived mediators like lipopolysaccharide (LPS) contributing to the disease. Ferroptosis in the liver microenvironment is influenced by factors such as iron overload, redox metabolism, and PUFA-phospholipid metabolism. Ferroptosis targeting in preclinical models has shown promise in reducing steatosis, inflammation, and fibrosis in MASLD. Lipophilic radical trapping antioxidants (RTAs), such as vitamin E, ferrostatin-1, and liproxstatin-1, have been effective in inhibiting ferroptosis. However, the role of ferroptosis in MASH-related HCC is complex, as cancer cells may upregulate systemXc- to avoid spontaneous ferroptosis. IndFerroptosis, a type of regulated cell death driven by iron-catalyzed lipid peroxidation of polyunsaturated fatty acids (PUFA) in membrane phospholipids, plays a significant role in metabolic dysfunction-associated steatotic liver disease (MASLD). This review highlights the molecular mechanisms of ferroptosis in liver physiology, evidence of ferroptosis in human MASLD, and the results of ferroptosis targeting in preclinical models. Ferroptosis is implicated in the progression of MASLD, leading to liver fibrosis and hepatocellular carcinoma (HCC). The rewiring of redox, iron, and PUFA metabolism in MASLD creates a proferroptotic environment, contributing to HCC development. Ferroptosis induction may offer a promising approach to eradicate HCC, while its inhibition could alleviate MASH disease progression. Ferroptosis is characterized by the accumulation of lipid hydroperoxides, which can lead to cell death through direct or indirect mechanisms. The key regulators of ferroptosis include glutathione peroxidase 4 (GPX4), which detoxifies lipid hydroperoxides, and the systemXc- antiporter, which maintains glutathione (GSH) levels. Other membrane-residing reductants, such as ubiquinol and tetrahydrobiopterin (BH4), also protect against ferroptosis. Ferroptosis is distinct from apoptosis and other forms of regulated necrosis, as it involves the release of intracellular content and is morphologically and biochemically distinct. In MASLD, ferroptosis is associated with increased levels of oxidative phospholipid products, such as 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), which are markers of lipid peroxidation. Ferroptosis is also linked to the release of danger-associated molecular patterns (DAMPs), such as oxidized phospholipids (oxPL), which can promote inflammation and fibrosis. The gut-liver axis plays a crucial role in MASLD, with intestinal dysbiosis and gut-derived mediators like lipopolysaccharide (LPS) contributing to the disease. Ferroptosis in the liver microenvironment is influenced by factors such as iron overload, redox metabolism, and PUFA-phospholipid metabolism. Ferroptosis targeting in preclinical models has shown promise in reducing steatosis, inflammation, and fibrosis in MASLD. Lipophilic radical trapping antioxidants (RTAs), such as vitamin E, ferrostatin-1, and liproxstatin-1, have been effective in inhibiting ferroptosis. However, the role of ferroptosis in MASH-related HCC is complex, as cancer cells may upregulate systemXc- to avoid spontaneous ferroptosis. Ind