Myricone C, a novel neolignan from Myristica fragrans, induces ER stress-mediated apoptosis in gastric and colorectal cancer via ROCK inhibition

Gastric and colorectal cancers remain leading causes of cancer-related mortality worldwide, highlighting the need for novel therapeutic strategies. Here, we report the potent anticancer activity of myricone C (MyrC), a novel neolignan and diarylnonanoid derivative isolated from Myristica fragrans, as a potent anticancer agent against these malignancies in vitro and in vivo. MyrC exhibited significant cytotoxicity in human gastric and colorectal cancer cell lines (IC50 values: 2.1–9.8 µM). Mechanistic studies revealed that MyrC induces G1 phase cell cycle arrest (gastric cells), increases the apoptosis-associated sub-G1 fraction (colorectal cells), and triggers apoptosis. Comprehensive transcriptomic analysis (RNA-seq, GSEA), validated by targeted qPCR and Western blotting, demonstrated that MyrC robustly induces endoplasmic reticulum (ER) stress, activates the unfolded protein response (UPR) primarily via the PERK-eIF2α-ATF4-CHOP axis, and upregulates downstream pro-apoptotic signaling. Furthermore, in silico docking predicted, and in vitro kinase assays confirmed, that MyrC directly binds and potently inhibits ROCK1 and ROCK2 kinases (IC50 values: 206–247 nM), which are implicated in cancer progression and potentially influence ER stress responses. Importantly, MyrC significantly suppressed tumor growth in a gastric cancer xenograft model in vivo without overt toxicity. These findings establish MyrC as a promising therapeutic lead candidate for gastric and colorectal cancer.