This study investigates the role of lipopolysaccharide-binding protein (LBP) in regulating lipid droplet (LD) homeostasis under oxidative stress. LBP is upregulated in response to oxidative stress, and its trafficking through LDs is a key mechanism for modulating LD homeostasis. LBP induces lipid accumulation by controlling lipid-redox homeostasis, specifically by sorting unsaturated triglycerides (TGs) into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated TG accumulation by competing with phospholipids and regulating the shuttle of LBP from LDs via Peroxiredoxin 4 (PRDX4). Chronic stress upregulates LBP expression, leading to insulin resistance and obesity. The findings suggest that LBP acts as an antioxidant to control lipid homeostasis and defend against oxidative stress by coupling with redox signaling and lipid metabolism. The study provides insights into the molecular mechanisms underlying oxidative stress-induced metabolic dysfunction and suggests potential redox-based therapies for alleviating such conditions.This study investigates the role of lipopolysaccharide-binding protein (LBP) in regulating lipid droplet (LD) homeostasis under oxidative stress. LBP is upregulated in response to oxidative stress, and its trafficking through LDs is a key mechanism for modulating LD homeostasis. LBP induces lipid accumulation by controlling lipid-redox homeostasis, specifically by sorting unsaturated triglycerides (TGs) into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated TG accumulation by competing with phospholipids and regulating the shuttle of LBP from LDs via Peroxiredoxin 4 (PRDX4). Chronic stress upregulates LBP expression, leading to insulin resistance and obesity. The findings suggest that LBP acts as an antioxidant to control lipid homeostasis and defend against oxidative stress by coupling with redox signaling and lipid metabolism. The study provides insights into the molecular mechanisms underlying oxidative stress-induced metabolic dysfunction and suggests potential redox-based therapies for alleviating such conditions.