Asporin promotes gastric cancer progression by regulating NRF2 ubiquitination and competitively binding to KEAP1.

Background: Extensive research into the molecular mechanisms of asporin (ASPN) has yielded valuable insights into cancer-targeted therapies. However, its specific roles and underlying mechanisms in gastric cancer (GC) progression remain poorly understood and present significant challenges. In this study, we conducted a comprehensive investigation into the molecular functions of ASPN and systematically evaluated its therapeutic implications in GC. Methods: Bioinformatics analysis and western blotting were employed to assess ASPN expression levels in GC tissues. Functional in vitro experiments were carried out to evaluate the impact of ASPN on tumor proliferation and metastasis. Co-immunoprecipitation and ubiquitination assays were conducted to explore the interaction between ASPN and the KEAP1/NRF2 signaling pathway. Results: Clinical data demonstrated that ASPN expression was significantly elevated in GC patients compared to normal controls. ASPN gene silencing was successfully achieved, and stable MKN45 and MKN28 cell lines were established to investigate its functional role. Knockdown of ASPN significantly suppressed GC cell proliferation, migration, and invasion. Furthermore, ASPN depletion led to a marked reduction in NRF2 protein levels, while KEAP1 expression remained unchanged. Mechanistically, ASPN stabilized NRF2 by competitively binding to KEAP1, thereby inhibiting proteasomal degradation. Notably, NRF2 overexpression partially reversed the inhibitory effects of ASPN knockdown on cell proliferation and invasion, highlighting the pivotal role of NRF2 in ASPN-mediated oncogenesis. Conclusions: Taken together, these findings demonstrate that ASPN facilitates GC cell proliferation and invasion through modulation of the KEAP1/NRF2 pathway, thereby identifying a crucial mechanism in GC progression. Targeting ASPN may represent a promising therapeutic approach for GC by disrupting this regulatory axis and reducing the protective effects of NRF2, ultimately enhancing tumor cell sensitivity to treatment.