SERPINA4 facilitates colorectal cancer progression through m⁶A-dependent stabilization.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. Serine protease inhibitors (SERPINs) have emerged as potential regulators in tumor progression, yet the specific function and regulatory mechanisms of SERPINA4 in CRC remain poorly characterized. METHODS: We integrated transcriptomic data from multiple CRC cohorts and conducted survival, pathway, and immune correlation analyses. Functional validation was performed using in vitro proliferation, migration, and invasion assays, as well as in vivo xenograft models. Post-transcriptional regulation of SERPINA4 via m6A modification was examined through MeRIP-qPCR, RNA immunoprecipitation, and decay assays. RESULTS: High expression of SERPINA4 was significantly associated with poor prognosis across multiple survival endpoints. SERPINA4 overexpression promoted CRC cell growth and metastasis in vitro and enhanced tumor formation in vivo. Mechanistically, ALKBH5-mediated m⁶A demethylation reduced SERPINA4 transcript stability by weakening IGF2BP3 association. Rescue experiments with methylation-deficient mutants confirmed the necessity of m6A for SERPINA4-driven oncogenicity. Moreover, SERPINA4 expression correlated with immunosuppressive signatures and reduced CD8 + T cell infiltration. CONCLUSIONS: Our findings reveal that SERPINA4 facilitates CRC progression through both tumor-intrinsic mechanisms and modulation of the immune microenvironment. These findings support an epitranscriptomic regulatory mechanism involving an ALKBH5–m6A–IGF2BP3 axis in CRC. SERPINA4 may serve as a prognostic biomarker and therapeutic target in precision oncology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-026-07810-1.