Wogonin suppresses colorectal carcinogenesis by dually targeting the gut microbiota and host PLCγ1-dependent signaling

The global burden of colorectal cancer (CRC) underscores the urgent need for innovative intervention strategies targeting the complex host-microenvironment interactions. The natural flavonoid wogonin (Wog) emerges as a promising candidate; however, its mechanism of action in CRC remains unclear. Here, using murine models of chronic colitis and colitis-associated cancer, we demonstrate that Wog ameliorates intestinal inflammation and tumorigenesis. Multi-omics analyses revealed that Wog concurrently restructures the gut microbiota and significantly reduces fecal levels of diacylglycerol (DAG), an oncogenic lipid second messenger. Importantly, Wog remained effective in microbiota-depleted mice and continued to reduce intestinal DAG levels, indicating a direct host-targeted mechanism. Further investigation identified phospholipase Cγ1 (PLCγ1) as a crucial mediator, with Wog directly binding to Arg116 of PLCγ1, thereby inhibiting its phosphorylation and subsequent host-derived DAG production. This interaction ultimately suppresses the protein kinase Cα (PKCα)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling cascade. The significance of this mechanism was confirmed by the loss of Wog's efficacy following PLCγ1 knockdown or Arg116 mutation. Our findings establish Wog as a dual-action agent that integrates microbiota remodeling with direct PLCγ1 inhibition, presenting a novel strategy for CRC interception.