International Immunopharmacology · Nov 13, 2026

Formononetin attenuates senescence-associated changes in models of gastric precancerous lesions: CALML4 as a candidate molecule

By Lai Y, Zhang S, Xie Z et al.

Background The transition from chronic gastritis to gastric cancer is a multistep process driven by persistent inflammation, yet the molecular mechanisms linking inflammation to epithelial transformation remain incompletely defined. Cellular senescence has been increasingly implicated in this process. Methods Integrative transcriptomic analyses were performed to identify conserved molecular features across chronic atrophic gastritis and early gastric cancer. Candidate molecules were further examined in human gastric biopsy specimens, an H. pylori/MNU-exposed mouse model, and GES-1 and AGS cell models. Results Integrated analyses implicated senescence- and inflammation-related pathways in Chronic atrophic gastritis (CAG) and Early gastric cancer (EGC) and prioritized CALML4 as a candidate gene. CALML4 expression was examined in mouse gastric tissues and human CAG and IM specimens. CALML4 knockdown reduced colony formation, migration, and invasion in H. pylori/MNU-exposed GES-1 cells and H. pylori-infected AGS cells. Computational analyses predicted a potential interaction between formononetin and CALML4, while CETSA results were consistent with increased thermal stability of CALML4 following formononetin treatment. In H. pylori/MNU-exposed mice, formononetin alleviated gastric histopathological changes and reduced CALML4 expression. In GES-1 cells, formononetin decreased SA-β-gal positivity and the expression of p16, p21, IL-6, and IL-8 after H. pylori/MNU exposure. It also reduced colony formation, migration, and invasion in both cell models. Conclusion CALML4 emerged as a candidate molecule associated with gastric epithelial alterations. Formononetin attenuated senescence-associated changes in the injured GES-1 model, while formononetin treatment and CALML4 knockdown each reduced the examined cellular behaviors. Whether the effects of formononetin depend on CALML4 remains to be established.

doi.org/10.1016/j.intimp.2026.117642PubMed 43025083Interventions