MZF1 Inhibits TGFβ-1/SMAD Signaling by Transcriptionally Activating SnoN to Augment Tumorigenic Potential in Colon Cancer.

Colon cancer progression is associated with transcriptional and signaling abnormalities. MZF1, linked to leukemogenesis, has an unclear role in colon cancer. This study examined its function in colon tumorigenesis and signaling-targeted therapies. Multi-omics (RNA-seq, CUT&Tag) identified MZF1 targets, validated in vitro/in vivo using xenografts and epithelial-specific MZF1 knockout mice. Virtual screening found MZF1 inhibitors. MZF1 activated SnoN transcription, suppressing TGF-β/SMAD signaling. Overexpression enhanced proliferation and colony formation; knockdown reversed these. In vivo, MZF1-overexpressing xenografts grew faster with more Ki67+ cells, while MZF1-/- mice had reduced tumor burden. Organoids from MZF1-/- mice grew poorly. 10Panx Acetate, an MZF1 inhibitor, disrupted MZF1-SnoN interaction, inhibiting cell and xenograft growth. Our results indicate MZF1 as a key colon cancer regulator via SnoN-mediated TGF-β pathway suppression and suggest 10Panx Acetate for precision therapy. MZF1/SnoN co-expression may predict aggressive disease.