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Life sciences · Journal article
Gut · October 12, 2026
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Background The hyperactivation of the Wnt/β-catenin pathway, which is driven primarily by Adenomatous polyposis coli (APC) mutations, is a hallmark and driver of colorectal cancer (CRC). Conventional feedback mechanisms are bypassed in APC-mutant CRC, highlighting the need for alternative mechanisms to restrain Wnt hyperactivation. Objective To identify and characterise a nuclear Wnt negative-feedback loop (nuNFL) that remains functional in both APC-wild-type and APC-mutant CRC, restrains Wnt/β-catenin hyperactivation downstream of APC and provides a strategy for overcoming the limitations of existing Wnt negative-feedback mechanisms in APC-mutant CRC. Design CRISPR/Cas9 screening and RNA-seq were integrated to identify regulators of Wnt/β-catenin downstream of APC. Conditional knockout mice were used to determine the role of basic helix-loop-helix family member e40 (BHLHE40). The therapeutic efficacy of BHLHE40 gene delivery, Photorhabdus virulence cassette nanoparticles loaded with BHLHE40 protein cargo (PVC-BHLHE40), and nanoparticle-mediated delivery of the BHLHE40-stabilising peptide P4.3 (P4.3-NPs) was evaluated. Leveraging the rhythmic expression of BHLHE40, we established P4.3-NP chronotherapy by administering P4.3-NPs at the peak of BHLHE40 expression. Results The Wnt/β-catenin target gene c-MYC transcriptionally upregulated BHLHE40, which repressed LEF1, establishing a ‘Wnt-c-MYC-BHLHE40-LEF1’ nuNFL. Despite elevated expression in CRC, BHLHE40 functioned as a tumour suppressor, as BHLHE40 loss accelerated CRC progression. nuNFL-boosting therapies suppressed Wnt/β-catenin signalling, eliminated cancer stem cells (CSCs) and prevented metastasis and relapse across diverse CRC models. P4.3-NP chronotherapy achieved superior tumour suppression and prevented relapse by targeting therapy-resistant CSCs. Conclusion BHLHE40-mediated nuNFL constitutes a critical regulatory layer that restrains Wnt/β-catenin signalling and provides a promising chronotherapeutic strategy for CRC treatment and recurrence prevention.