LL-37 inhibits osteosarcoma progression by suppressing SQLE-mediated cholesterol synthesis via PTEN/AKT/mTOR

Osteosarcoma (OS) is an aggressive primary bone malignancy with a poor prognosis, especially for metastatic or recurrent cases, highlighting an urgent need for novel therapeutic strategies. Current standard-of-care, involving surgery and chemotherapy, often falls short, leading to suboptimal patient survival rates. The human cathelicidin peptide LL-37, known for its context-dependent anti-tumor effects, presents a potential new avenue, but its specific functional role and underlying mechanisms in OS have remained largely undefined until now. This study addresses this critical gap.

Researchers conducted in vitro experiments using osteosarcoma cell lines (e.g., 143B) and normal human bone marrow mesenchymal stem cells (hBMSCs) to evaluate cell viability, clonogenic survival, migration, invasion, cell cycle distribution, cell death, and cholesterol metabolism. Transcriptomic profiling, siRNA-mediated knockdown, plasmid overexpression, and rescue experiments were employed to validate key signaling pathways. The in vivo therapeutic efficacy of LL-37 was assessed using a 143B cell xenograft model in mice, comparing its effects to cisplatin.

LL-37 selectively inhibited the viability of OS cells while showing minimal toxicity to hBMSCs. It significantly suppressed clonogenic survival, migration, and invasion, and induced S-phase cell cycle arrest. LL-37 also triggered both mitochondrial apoptosis and caspase-1/GSDMD-dependent pyroptosis. Transcriptomic analysis revealed cholesterol biosynthesis as a key pathway downregulated by LL-37, with the rate-limiting enzyme squalene epoxidase (SQLE) markedly reduced. > Mechanistically, LL-37 upregulated the tumor suppressor PTEN, thereby inhibiting the AKT/mTOR pathway and suppressing SREBP2/SQLE-mediated cholesterol synthesis. Rescue experiments confirmed that SQLE inhibition was required for LL-37's pro-apoptotic effects. In vivo, LL-37 dose-dependently inhibited the growth of OS xenografts, demonstrating efficacy comparable to cisplatin without causing obvious systemic toxicity.