Asiatic acid remodels the gastric precancerous immune microenvironment by targeting STING

Chronic inflammation-driven gastric precancerous lesions (GPL) are characterized by progressive immune remodeling toward an immunosuppressive state, yet effective chemopreventive agents targeting this process remain scarce. Here, we identify asiatic acid (AA), a natural pentacyclic triterpenoid, as a STING‑binding compound that contributes to reshaping the gastric immune microenvironment and interfering with the Correa cascade.

Using a rat model of MNNG‑induced GPL (atrophy, intestinal metaplasia, dysplasia) and MNNG‑treated GES‑1 cells, we assessed histopathological damage, systemic pro‑inflammatory cytokines (TNF, IL‑6, MCP1), and gastric physiological function. STING binding was evaluated by surface plasmon resonance (SPR) with KD measurement and 100 ns molecular dynamics simulations. The cGAS-STING-TBK1-IRF3 axis was examined in vivo and in vitro. Gut microbiota was analyzed by 16S rRNA sequencing, and the Nrf2-Keap1 antioxidant pathway, mitochondrial membrane potential, and oxidative stress were measured. Rescue experiments were performed using the STING agonist cGAMP.

AA ameliorated histopathological damage, exerted regulatory effects on systemic pro‑inflammatory cytokines with a non‑linear dose‑response pattern, and improved gastric physiological function. Mechanistically, AA directly bound to STING with a KD of 4.0 μM and maintained a stable conformation in simulations, suppressing aberrant activation of the cGAS-STING-TBK1-IRF3 axis. AA also reversed gut microbiota dysbiosis (notably reducing pro‑inflammatory Erysipelotrichales), restored the Nrf2-Keap1 pathway, improved mitochondrial membrane potential, and reduced oxidative stress. Rescue experiments with cGAMP partially abolished AA's protective effects, supporting the functional involvement of STING signaling in AA's actions.

Collectively, AA interrupts the vicious "microbiota-oxidative stress-STING" loop in a STING‑dependent manner and contributes to remodeling the precancerous immune microenvironment, positioning it as a promising chemopreventive candidate targeting the earliest phase of gastric carcinogenesis.