Lysine-Proline-Valine attenuates oxidized low-density lipoprotein-induced foam cell formation and inflammatory...

Atherosclerosis develops through oxidative stress and inflammatory responses induced by oxidized low-density lipoprotein (oxLDL), and excessive lipid accumulation in macrophages accelerates disease progression by facilitating foam cell formation. In this study, we investigated the protective effects of the α-melanocyte-stimulating hormone-derived endogenous tripeptide Lysine-Proline-Valine (KPV) against oxLDL-induced cellular injury in RAW264.7 macrophages. Exposure to oxLDL markedly increased lipid accumulation in RAW264.7 macrophages, concomitantly enhancing inflammatory signaling and promoting foam cell formation. Treatment with KPV significantly attenuated oxLDL-induced lipid accumulation, thereby suppressing foam cell formation, while also suppressing inflammatory responses without inducing cytotoxicity. Mechanistic analyses revealed that KPV reduced intracellular reactive oxygen species (ROS) levels, thereby suppressing the activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB), which serve as key regulators of Interleukin-1β (IL-1β) expression. In addition, KPV suppressed the assembly of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, leading to a reduction in apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, caspase-1 cleavage, and IL-1β maturation. These findings suggest that KPV functions as an effective modulator of oxidative stress and inflammatory signaling and may hold substantial therapeutic potential for suppressing foam cell formation and attenuating disease progression in atherosclerosis.