The study shows that the natural peptide LL‑37 can latch onto LDL (bad cholesterol) and make it easier for the liver and immune cells to pull it out of the bloodstream, helping clear cholesterol and prevent fat buildup in the liver in mice. While this points to a new way the body might naturally manage cholesterol, it’s still early‑stage research and not yet a ready‑to‑use protocol for people.

Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe^-/- mice with hypercholesterolemia, the murine homolog cathelicidin Cramp similarly accelerates cholesterol clearance by activating cholesterol excretion and preventing hepatic lipid accumulation. This study identifies LL-37 as an endogenous regulator of LDL that promotes LDL cholesterol clearance.