CHPF2-driven chondroitin sulfation of Wnt1 promotes colorectal cancer progression and is targeted by ponicidin

Phytomedicine. 2026 Jun 29;159:158528. doi: 10.1016/j.phymed.2026.158528. Online ahead of print.

ABSTRACT

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death worldwide, mainly due to cancer cell proliferation and migration. Although chondroitin sulfate (CS) is involved in cancer progression, its regulatory mechanisms remain unclear.

PURPOSE: To investigate the role and mechanism of chondroitin polymerizing factor 2 (CHPF2) and CS in CRC progression, as well as to evaluate the therapeutic potential of ponicidin.

METHODS: The correlation between CHPF2 and prognosis was analyzed in clinical samples. Mechanistically, ponicidin was found to target CHPF2, suppress CS synthesis, and consequently block the Wnt/β-catenin pathway. Its anti-tumor efficacy was validated in cellular, organoid, and animal models.

RESULTS: We identified CHPF2, a key enzyme in CS synthesis, as a critical driver of CRC. CHPF2 is significantly overexpressed in CRC tissues, and its high expression correlates with advanced disease stage and poor patient prognosis. Functionally, CHPF2 drives tumor cell proliferation, migration, and survival by enhancing CS production. Mechanistically, CS promotes the activation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT). This effect is associated with CS-dependent modifications of Wnt1; however, further investigation is required to determine whether Wnt1 is directly modified by CS chains or indirectly affected via CS-modified proteoglycans. Furthermore, the natural diterpenoid ponicidin derived from Rabdosia rubescens directly targets CHPF2 and inhibits its enzymatic activity, thereby reducing CS biosynthesis and subsequently blocking the Wnt/β-catenin signaling pathway. The anti-tumor efficacy of ponicidin was validated in cellular models, patient-derived organoids, and primary CRC models, demonstrating its potent inhibitory effects on tumor growth and metastasis.

CONCLUSION: Our study reveals the oncogenic role of the CHPF2/CS axis in CRC, establishes CHPF2 as a novel therapeutic target, and provides compelling preclinical evidence supporting ponicidin as a promising CHPF2-targeted agent for CRC treatment.

PMID:42401071 | DOI:10.1016/j.phymed.2026.158528