Ubiquitination-Dependent Cyclin Regulation in Gastric Cancer and Emerging Targeted Therapies with Chinese Herbal Bioactive Compounds.

Gastric cancer (GC) remains one of the most prevalent malignancies worldwide, with a high mortality rate primarily attributable to late-stage diagnosis and limited therapeutic options. Aberrant cell proliferation arising from cell cycle dysregulation is a hallmark of GC pathogenesis. Cyclins, as core regulators of cell cycle progression, exhibit dynamic protein expression patterns that are tightly controlled by the ubiquitin-proteasome system (UPS). In GC, cyclins are frequently overexpressed due to impaired ubiquitination and subsequent proteasomal degradation. This review systematically elucidates the ubiquitination-mediated regulation of distinct cyclins (Cyclins D, E, A, and B) at specific cell cycle phases-G1, S, G2, and M-and highlights the critical roles of E3 ubiquitin ligases, including SCF complexes and APC/C, in GC progression. We further discuss how dysregulated non-coding RNAs and altered E3 ligase expression contribute to aberrant cyclin ubiquitination, thereby promoting GC cell proliferation, metastasis, and poor prognosis. Importantly, emerging evidence demonstrates that bioactive compounds derived from traditional Chinese medicine (TCM) can counteract these abnormalities by directly downregulating cyclin expression, modulating E3 ligase activity, or inhibiting 26S/20S proteasome function, thus restoring cell cycle homeostasis and suppressing GC growth. This review integrates molecular mechanisms of cyclin ubiquitination with TCM-based therapeutic strategies, offering novel insights into targeted interventions for GC.