GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE342nnn/GSE342138/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE342138GEOGSEfalseSynthesis and Mechanistic Dissection of Biselyngbyaside Induced Cytotoxicity through Multi-omics ProfilingDeciphering the mechanism of action of natural products remains great challenges. 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.2026/08/31GSE342138GSM9923736GSM9923737GSM9923738GSM9923739GSM9923740GSM9923741GSM9923742GSM9923743GSM992374424676342138Homo sapiens