Lipopolysaccharide-binding protein (LBP) regulates lipid droplet (LD) homeostasis to resist hepatic oxidative stress. Under oxidative stress, LBP enhances lipid accumulation by capturing unsaturated triglycerides (TGs) and sequestering them into LDs, preventing lipolysis and peroxidation. LBP's lipid-capture activity is regulated by its interaction with peroxiredoxin 4 (PRDX4), a redox sensor that controls LBP's shuttle between LDs. Chronic stress increases LBP expression, leading to insulin resistance and obesity. LBP's role in LD homeostasis and antioxidant defense is crucial for preventing oxidative injury. Antioxidant treatment, such as N-acetyl-L-cysteine (NAC), reduces LBP-mediated TG accumulation by competing with phospholipids and promoting LBP exit from LDs. LBP's interaction with PRDX4 is essential for its function, as PRDX4 senses oxidative stress and facilitates LBP's exit from LDs, promoting lipolysis. LBP's C-segment hydrophobic groove and #4-helix are critical for binding oxidized TGs, enhancing its antioxidant capacity. LBP's expression is regulated by redox signals, and its upregulation contributes to metabolic dysfunction and obesity. Chronic stress increases LBP levels, which may mediate TG accumulation and obesity. Antioxidant therapy shows promise for treating LBP-induced metabolic disorders. This study highlights LBP's role in lipid metabolism and redox signaling, offering insights into potential therapeutic strategies for oxidative stress-related diseases.Lipopolysaccharide-binding protein (LBP) regulates lipid droplet (LD) homeostasis to resist hepatic oxidative stress. Under oxidative stress, LBP enhances lipid accumulation by capturing unsaturated triglycerides (TGs) and sequestering them into LDs, preventing lipolysis and peroxidation. LBP's lipid-capture activity is regulated by its interaction with peroxiredoxin 4 (PRDX4), a redox sensor that controls LBP's shuttle between LDs. Chronic stress increases LBP expression, leading to insulin resistance and obesity. LBP's role in LD homeostasis and antioxidant defense is crucial for preventing oxidative injury. Antioxidant treatment, such as N-acetyl-L-cysteine (NAC), reduces LBP-mediated TG accumulation by competing with phospholipids and promoting LBP exit from LDs. LBP's interaction with PRDX4 is essential for its function, as PRDX4 senses oxidative stress and facilitates LBP's exit from LDs, promoting lipolysis. LBP's C-segment hydrophobic groove and #4-helix are critical for binding oxidized TGs, enhancing its antioxidant capacity. LBP's expression is regulated by redox signals, and its upregulation contributes to metabolic dysfunction and obesity. Chronic stress increases LBP levels, which may mediate TG accumulation and obesity. Antioxidant therapy shows promise for treating LBP-induced metabolic disorders. This study highlights LBP's role in lipid metabolism and redox signaling, offering insights into potential therapeutic strategies for oxidative stress-related diseases.