Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming increasingly more prevalent and poses a major growing health concern worldwide. Iron deposition have been observed in the liver of MASLD patients and iron can lead to the formation of reactive oxygen species. Although lipids were altered Journal Pre-proof in the livers of MASLD patients, the underlying mechanisms implicated in this disease have not yet been fully elucidated. Comprehensive lipidomics analysis revealed that elevated GM3 levels resulting in abnormal lipid metabolism in the HCD-fed mice decreased after DFO treatment and dietary intervention. Proteomics analysis uncovered significant decreases in the expression levels of hepatic proteins involved in both biosynthesis and uptake of fatty acid and cholesterol after DFO treatment. These results were verified with isotope labeled oleic acid and/or cholesterol uptake assay. Furthermore, the iron chelating properties of DFO alleviated oxidative stress induced by HCD. The pathways of “Cytoplasmic ribosomal proteins”and “G13 signaling” were restored after DFO treatment and dietary intervention. The combinatorial synergistic effect of diet and DFO successfully restored LPC and GM3 levels back to almost control levels in MASLD mice as well as restored lipid and protein homeostasis. Ultimately, culminating in the alleviation of MASLD triggered dysregulated pathway.