Coupling Dysfunction of Mitochondria and Actin in Loss of Native Gastric Glands: A Mechanistic Hypothesis for Chronic Atrophic Gastritis Pathogenesis

The progressive loss of native gastric glands in chronic atrophic gastritis (CAG) represents a critical step toward gastric carcinogenesis, yet the underlying cellular structural mechanisms remain incompletely understood. In this review, we formulate an integrative mechanistic hypothesis that disruption of actin cytoskeletal homeostasis, driven by mitochondrial bioenergetic dysfunction, plays a central role in the progressive loss of native gastric glands. Persistent H. pylori infection and chronic mucosal inflammation may initiate a self-reinforcing cycle of metabolic and structural impairment: mitochondrial ATP depletion compromises the energy supply required for F-actin polymerization, whereas oxidative stress promotes aberrant activation of the cofilin pathway, resulting in increased filament disassembly. This imbalance in the energy–cytoskeleton axis may impair epithelial polarity signaling and mechanotransduction, thereby contributing to stem cell dysregulation and progressive mucosal degeneration. While this synthesis relies primarily on in vitro and multi-omics evidence, it provides a complementary perspective on CAG pathogenesis and highlights potential therapeutic strategies aimed at restoring cellular mechanical and metabolic homeostasis to prevent precancerous progression.