PSPC1-AS2/PSPC1 axis drives STAT3-dependent CCL2 expression to promote M2 macrophage polarization and liver metastasis in gastric cancer.

Liver metastasis is a major cause of mortality in gastric cancer (GC), yet the underlying molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression and cancer progression, but their roles in GC liver metastasis are not fully defined. In this study, lncRNA sequencing of primary GC tumors and matched liver metastatic tissues identified PSPC1-AS2 as significantly upregulated. Its elevated expression was further validated across multiple patient cohorts and public datasets. Functional assays demonstrated that PSPC1-AS2 promotes GC cell migration, invasion, and liver metastasis both in vitro and in vivo. Mechanistically, PSPC1-AS2 is predominantly localized in the nucleus and enhances the mRNA stability of its neighboring gene PSPC1 by recruiting the RNA-binding protein EIF4A3. The PSPC1-AS2/PSPC1 axis facilitates tumor progression and induces macrophage polarization toward the pro-tumorigenic M2 phenotype via increased CCL2 secretion. At the molecular level, PSPC1 interacts with PARP1, competitively inhibiting PARP1-mediated PARylation and dephosphorylation of STAT3, thereby sustaining STAT3 activation and promoting CCL2 transcription. Notably, neutralization of CCL2 effectively reverses PSPC1-induced M2 macrophage polarization. Collectively, these findings reveal a novel PSPC1-AS2/PSPC1/STAT3/CCL2 regulatory axis that drives GC progression and liver metastasis through remodeling of the tumor microenvironment, highlighting a potential therapeutic target for advanced gastric cancer.