Renqing Mangjue modulates chronic atrophic gastritis inflammation-cancer transition via the cGMP–PKG/PI3K–AKT pathway

Abstract Background Chronic atrophic gastritis (CAG) is a critical stage in the progression from inflammation to cancer and is closely associated with an increased risk of gastric cancer (GC). Renqing Mangjue (RQMJ), a traditional Tibetan herbal remedy, has shown diverse pharmacological properties, including regulation of gastrointestinal function and anti-inflammatory effects. However, the specific effects and mechanisms by which RQMJ influences the transition from inflammation to cancer remain unclear. Objectives This study aimed to evaluate the preventive and therapeutic effects of RQMJ on CAG and its intervention in the inflammation–cancer transition process, with a focus on exploring the underlying molecular mechanisms. Methods RQMJ was chemically characterized by UPLC-Q-TOF–MS/MS and HPLC. A rat model of CAG and its inflammation-cancer transition was established and treated with different doses of RQMJ. The therapeutic effects of RQMJ were evaluated by gross gastric mucosal observation, ELISA, histopathological staining, immunohistochemistry, and Western blot analysis. In vitro, the effects of RQMJ on inflammation and migration of the gastric precancerous cell model (MC cells) were assessed using ELISA, wound-healing, Transwell migration, and Western blot assays. RNA sequencing and molecular biology techniques were then employed to explore the underlying mechanisms, and key targets were further validated in both in vivo and in vitro experiments. Finally, C-type natriuretic peptide (CNP) was used to verify the involvement of the identified signaling pathway. Results A total of 2780 chemical constituents were identified in RQMJ. A dynamic rat model of CAG and its progression to GC was established. During CAG, persistent inflammation and aberrant PI3K–AKT activation formed a positive-feedback loop, driving FAK overexpression and epithelial–mesenchymal transition (EMT)-related changes, which remained active in GC despite partial reduction of inflammation. RQMJ markedly alleviated gastric mucosal injury, suppressed intestinal metaplasia, and improved gastrointestinal function. It also reduced pro-inflammatory mediators (TNF-α, IL-1β, CRP), increased IL-10, and downregulated tumor-related markers (Ki-67, Vimentin, CA19-9). In vitro, RQMJ inhibited MC cell proliferation and migration, suppressed inflammatory and EMT-related proteins. Mechanistically, RQMJ activated the cGMP–PKG pathway and inhibited the PI3K–AKT signaling pathway, thereby disrupting inflammatory amplification. This further downregulated extracellular matrix (ECM)–receptor interaction molecules (TGF-β, FAK, Itga2), ultimately blocking the inflammation–cancer transition. Conclusion RQMJ may activate the cGMP–PKG signaling pathway while suppressing aberrant PI3K–AKT activation, thereby reducing inflammatory cytokine levels and inhibiting ECM remodeling and the EMT-associated process, and thus indirectly interrupting the inflammation - cancer cascade. These findings highlight the potential pharmacological value and therapeutic prospects of RQMJ in inflammation-driven gastric diseases.