Synthesis and Mechanistic Dissection of Biselyngbyaside Induced Cytotoxicity through Multi-omics Profiling

Biselyngbyasides (BILs), a class of marine 18-membered macrolides, display strong cytotoxicity in various cancer cells, whereas, their molecular mechanisms remain poorly understood. Here, we establish a multi-omics strategy integrating chemotranscriptomics, phosphoproteomics and peptide-centric local stability assays (PELSA) to systematically characterize cellular responses triggered by biselyngbyolide A (BILA).

Multi-omics data analysis demonstrates that BILA triggered a signaling cascade including ER stress, UPR activation, lipid metabolism remodeling, cell-cycle arrest, and apoptosis by inhibition of SERCA. Using synthetic BILA and its aza-analogue, we performed structure-function analysis and further pinpoint the core pharmacophore responsible for cytotoxicity. This study clarifies the full signaling network regulated by BILA and provides a versatile analytical tools for mechanistic investigation of complex natural products in early drug discovery.