PJA2 is documented to degrade various substrates. Nevertheless, the role of PJA2 as an E3 ubiquitin-protein ligase in colorectal cancer (CRC) progression remains unexplored. The correlation between PJA2 mRNA levels and clinical characteristics is investigated using data from The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) are utilized to evaluate PJA2 expression levels in CRC tissues. The biological functions of PJA2 are confirmed through colony formation assays and azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model of CRC, among other experimental approaches. The underlying molecular mechanisms of PJA2 action are elucidated using RNA sequencing (RNA-seq), co-immunoprecipitation (co-IP), proximity ligation assay (PLA), and chromatin immunoprecipitation (ChIP). Our research discovered that PJA2 is downregulated in CRC tissues and decreased PJA2 expression correlates with poor prognosis. Functionally, in vivo and in vitro experiments uncovered that PJA2 inhibits tumor cell proliferation and promotes apoptosis. Mechanistically, PJA2 recognized histone deacetylase 2 (HDAC2) via its RING-B-box domain (RBD) and bind to the N-terminal of HDAC2, facilitating ubiquitination at the lysine 90 (K90) residue. PJA2-mediated degradation of HDAC2 counteracts the transcriptional repression of the interferon-induced protein with the tetratricopeptide repeats (IFIT) family, thereby suppressing CRC progression. The data demonstrates that PJA2 suppresses CRC progression through the PJA2/HDAC2/IFIT axis, and its expression is regulated by HDAC2, thus constituting a positive feedback loop. Consequently, PJA2 may serve as a potential therapeutic target for CRC, and interrupting this feedback loop can represent a viable treatment strategy to restrain CRC progression.