Targeting the Correa’s cascade of gastric cancer: the potential role of phytochemicals and autophagy modulation

Gastric cancer (GC) development follows a sequential and complex pathophysiological process known as Correa’s cascade, progressing from chronic gastritis (active or inactive) to precancerous lesions (intestinal metaplasia (IM) and dysplasia) and ultimately to adenocarcinoma. Current GC therapies have limited efficacy and high recurrence rates. Autophagy, a cellular self-degradation mechanism that removes damaged or harmful components, plays a critical role in maintaining cellular homeostasis. Phytochemicals, owing to their low toxicity and multi-target pharmacological properties, exhibit anti-inflammatory, antimicrobial, antioxidant, and anticancer activities, and certain phytochemicals have shown potential in suppressing GC progression. In the inflammatory stage, metabolites such as berberine (an alkaloid) and chlorogenic acid (a phenolic acid) modulate autophagy by regulating the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway: upstream activation of PI3K leads to AKT phosphorylation, which subsequently inhibits the downstream autophagy-related genes Unc-51-like kinase ( ULK1 ) and Beclin-1, while these phytochemicals can reverse this inhibition to reduce inflammatory cytokine secretion and promote ulcer healing. In the precancerous stage, agents such as ginsenoside Rg3 and astragaloside IV (terpenoids) regulate autophagy through the PI3K/AKT axis and by influencing p62/sequestosome 1 (SQSTM1), an autophagy adaptor that links upstream microtubule-associated protein 1 light chain 3 (LC3)-interacting partners to downstream ubiquitinated substrates—thereby restoring autophagic flux and preventing malignant transformation. In the cancer stage, phytochemicals from various subclasses (phenolics, alkaloids, and terpenoids) target the core autophagy machinery: they suppress upstream PI3K/AKT/mTOR signaling (with mTOR directly inhibiting the initiation complex formed by ULK1, ATG13, and FIP200), induce the expression of Beclin-1 and ATG family proteins, promote the conversion of LC3-I to LC3-II, and enhance autophagosome formation. Consequently, these metabolites inhibit GC cell proliferation, migration, and angiogenesis while inducing apoptosis and increasing chemosensitivity. From a clinical translation perspective, the consistent observation that pharmacological inhibition of cytoprotective autophagy enhances phytochemical-induced apoptosis suggests a rational combination strategy: pairing a phytochemical that induces cytoprotective autophagy with an approved autophagy inhibitor such as hydroxychloroquine. This approach has been tested in vitro for curcumin, quercetin, and berberine but not yet in animal models or clinical trials. Given the established safety profiles of these agents individually, such combinations could be rapidly tested in preclinical gastric cancer models and, if successful, progressed to early-phase clinical trials as adjuncts to standard chemotherapy. Moreover, ongoing clinical trials of berberine for gastrointestinal metaplasia and of resveratrol for chemotherapy toxicity reduction provide existing clinical frameworks onto which autophagy endpoint measurements could be incorporated. These findings highlight the potential of autophagy-targeting phytochemicals as promising strategies for GC prevention and treatment, offering valuable insights for clinical translation. Moreover, targeting autophagy with phytochemicals represents a promising avenue for future drug development, potentially enabling personalized combination therapies to overcome chemoresistance and improve long-term outcomes for patients with gastric cancer.