ZC3H13-driven m6A methylation of P4HA3 enhances gastric cancer tumorigenesis via interacting with IGF2BP1

Gastric cancer (GC) is one of the primary contributors to cancer-associated deaths worldwide due to its aggressive progression and limited effective therapeutic strategies. Increasing evidence suggests that N6-methyladenosine (m 6 A) RNA methylation contributes to GC development, although its downstream targets are not fully understood. This study explores the biological role of prolyl 4-hydroxylase subunit alpha 3 (P4HA3) and regulation by m 6 A methylation. Bioinformatic analyses of public datasets identified prognosis-related genes in GC. P4HA3 silencing experiments in GC cell lines and mouse xenograft models evaluated its influence on proliferation, migration, invasion, and tumor growth in vivo. Interactions among P4HA3, ZC3H13, and IGF2BP1 were examined using qRT-PCR, western blotting, MeRIP, mRNA stability, RIP, and dual-luciferase reporter assays. Rescue experiments were performed to assess whether GC malignancy depended on the ZC3H13–P4HA3 regulatory axis. Bioinformatic analyses identified P4HA3 as an upregulated gene in GC associated with poor overall survival. P4HA3 silencing suppressed GC cell malignant properties, and tumor growth in vivo. Mechanistically, ZC3H13 overexpression increased P4HA3 mRNA and protein levels by promoting m 6 A-dependent mRNA stability. ZC3H13-mediated m 6 A methylation facilitated IGF2BP1 binding to P4HA3 transcripts, sustaining its expression. Rescue assays showed that ZC3H13 restoration partly reversed the effects of P4HA3 silencing via PI3K/AKT signaling pathway. In addition, GEPIA analysis revealed that ZC3H13–IGF2BP1–P4HA3 axis exhibited clinical prognostic relevance in GC. This work identifies P4HA3 as an m 6 A-regulated oncogene in GC and reveals a ZC3H13–IGF2BP1–P4HA3 axis that promotes tumor progression, providing a probable therapeutic target.