ZNF33A activates Wnt/β-catenin signaling and promotes BCAA catabolism in colorectal cancer

Aberrant activation of Wnt/β-catenin signaling is a hallmark of colorectal cancer (CRC), but the upstream regulators and associated metabolic consequences remain incompletely defined. Branched-chain amino acid (BCAA) metabolism has been implicated in CRC progression, yet its regulation and functional role remain controversial. This study investigates the role of the transcription factor ZNF33A in CRC pathogenesis. ZNF33A expression was examined in CRC tissues, cell lines, and public databases. Gain- and loss-of-function experiments were conducted in vitro (CCK8, EdU, soft agar, reporter assays, Co-IP, ChIP, BCAA assays) and in vivo (Lgr5-GFP mouse models and AOM/DSS-induced CRC). Statistical analyses included Student’s t-test, ANOVA, and Kaplan–Meier survival analysis. ZNF33A was significantly upregulated in CRC tissues and correlated with poor prognosis. Overexpression of ZNF33A promoted proliferation, colony formation, and BCAA consumption, while its down-regulation suppressed tumor growth, stemness, and organoid formation. Mechanistically, ZNF33A bound β-catenin, enhanced β-catenin/TCF transcriptional activity, and induced expression of BCAT1, a key BCAA-catabolizing enzyme. Suppression of β-catenin or BCAT1 abrogated ZNF33A-driven oncogenic effects. ZNF33A drives CRC progression by activating Wnt/β-catenin signaling and reprogramming BCAA metabolism via BCAT1. These findings identify ZNF33A as a potential therapeutic target and highlight BCAA metabolic modulation as a promising strategy for CRC treatment.