Colorectal cancer remains one of the most common malignancies worldwide, and China in particular faces a worsening epidemic marked by rising incidence. Surgery can cure early disease, but advanced patients depend on adjuvant chemotherapy to prevent recurrence. The mainstream FOLFOX and CAPOX regimens extend overall survival to nearly 20 months, with oxaliplatin acting as their platinum backbone. The drug interferes with DNA replication and transcription by forming platinum adducts on DNA. Yet colorectal tumors routinely develop resistance through enhanced DNA repair, heightened autophagy and increased drug efflux, among other mechanisms. This has fueled intense interest in small-molecule sensitizers that can be layered onto existing chemotherapy without adding excessive toxicity.

Ellagic acid has long been an intriguing candidate. It is a polyphenolic dilactone with the formula C14H6O8, bearing two lactone rings and four hydroxyl groups that confer potent antioxidant activity. In plants it exists mainly as ellagitannins, condensed structures that gut microbiota convert into ellagic acid, which is then readily absorbed thanks to its lower molecular weight. Herbal formulas rich in the compound, such as the classic Xihuang Pill, are already used alongside FOLFOX in China to treat colorectal cancer and prevent postoperative recurrence. Earlier laboratory work had shown that ellagic acid can synergize with the other core FOLFOX drug, 5-fluorouracil, but whether it could also sensitize tumors to oxaliplatin remained an open question.

To answer it, the team turned to two colorectal cancer cell lines, Caco-2 and SW48, both of which harbor wild-type TP53, the form of the gene found in roughly 57 percent of colorectal tumors. Cell viability assays and colony formation experiments showed that ellagic acid on its own suppressed proliferation and, when paired with oxaliplatin, produced a genuinely synergistic effect as measured by combination index analysis. At the concentrations selected for further study, 40 micromolar ellagic acid and 2 micromolar oxaliplatin, the polyphenol inhibited a normal colon epithelial cell line by only about 10 percent, suggesting a therapeutic window. Flow cytometry confirmed that the combination drove the highest rate of apoptosis, while oxaliplatin alone mostly stalled cells at the G2/M checkpoint of the cell cycle.

The mechanistic hunt began with an unbiased approach. Network pharmacology predicted that protein phosphorylation would be the dominant regulatory effect of ellagic acid, and a Human Phospho-Kinase Array then revealed that the compound increased the phosphorylation of p53 and p38 while dampening phosphorylated Erk1/2 and Chk2. That pattern pointed straight at Wip1, the wild-type p53-induced phosphatase 1 encoded by the oncogene PPM1D. Wip1 sits at the center of a negative feedback loop: p53 switches on Wip1 expression, but Wip1 in turn dephosphorylates and silences p53 and inactivates p38. Western blotting confirmed that ellagic acid inhibited Wip1 and boosted p-p53 and p-p38 in a dose-dependent fashion, although molecular docking found no direct binding between the polyphenol and Wip1, meaning the phosphatase was being suppressed indirectly.

The trail led upstream to ATM, the ataxia-telangiectasia mutated kinase that orchestrates the cellular response to DNA double-strand breaks. Surprisingly, ellagic acid inhibited ATM phosphorylation in a dose-dependent manner, while the combination with oxaliplatin enhanced phosphorylation of ATR, a related kinase that serves as a compensatory survival pathway when ATM signaling falters. Molecular docking predicted that ellagic acid binds ATM at the residues SER1801 and ARG2279, and the team verified physical interaction using co-immunoprecipitation with biotin-conjugated ellagic acid and a cellular thermal shift assay, which showed that the compound stabilizes the ATM protein. Genetic experiments sealed the argument: forcing ATM overexpression abolished the synergistic killing by the drug pair, while silencing ATM with shRNA attenuated oxaliplatin resistance, faithfully mimicking the effect of ellagic acid. Blocking the compensatory ATR pathway with the inhibitor M6620 likewise dismantled the synergy, underscoring how both arms of the DNA damage response shape the outcome.

The remaining puzzle was how suppressing ATM, an activator of p53, could still leave p53 empowered. The answer lay in an unexpected metabolic branch: ATM phosphorylates AMPK, which in turn phosphorylates HIPK2 at specific residues. Phosphorylated HIPK2 leaves the nucleus and loses the ability to bind Wip1, allowing Wip1 to escape degradation. When ellagic acid dampens ATM signaling, AMPK phosphorylation falls, HIPK2 stays in the nucleus where it tags Wip1 for ubiquitination and proteasomal destruction, and Wip1 levels collapse. With the brake released, p53 signaling surges, elevating p21 and shifting the Bax/Bcl-2 ratio toward apoptosis. Transfection experiments confirmed each link: overexpressing Wip1 erased the benefit of the combination, while knocking Wip1 down enhanced oxaliplatin’s efficacy on its own.

Clinical and animal data lent the mechanism real-world weight. Among 71 patients with stage III wild-type TP53 colorectal cancer who received postoperative FOLFOX chemotherapy at Tianjin Union Medical Center between 2015 and 2023, high Wip1 expression in tumor tissue correlated significantly with poorer overall and disease-free survival, whereas ATM expression varied little. The team then established patient-derived xenograft models using tumor tissue from three patients, one with high and one with low Wip1 expression. In the Wip1-high model, adding ellagic acid, dosed at 100 or 200 milligrams per kilogram daily alongside oxaliplatin every three days, effectively downregulated Wip1, reactivated p53 and sharpened the antitumor effect measured by Ki-67 and TUNEL staining. In the Wip1-low tumor, the polyphenol added little. The study was candid about safety limits: all mice receiving the highest combination dose died within two weeks from drug toxicity, and hepatic injury appeared when the ellagic acid dose exceeded 160 milligrams per kilogram per day, leading the authors to designate the 100 milligram per kilogram regimen as relatively safe.

The findings carry several caveats that the researchers themselves acknowledge. The work was restricted to wild-type TP53 tumors to avoid confounding, since mutant p53 rewires the Wip1 relationship entirely. Ellagic acid is also metabolized by gut bacteria into urolithin A, which acts through distinct mechanisms, and individuals of the UM-0 metabotype cannot produce urolithin A at all, so the contribution of these metabolites in different patients remains to be clarified. Liquid chromatography-mass spectrometry did confirm that ellagic acid is detectable in the circulation of a patient taking Xihuang Pill, lending clinical plausibility to the adjuvant strategy. Wip1 inhibitors have generally shown weak activity alone but real promise in combination, and this study suggests that Wip1 expression could serve as a biomarker to guide which patients benefit when ATM-targeting agents are added to platinum chemotherapy. If larger studies bear out the safety and synergy, ellagic acid or ellagitannin-rich herbal formulations could become a low-cost adjunct to FOLFOX, precisely tailoring a decades-old regimen to the molecular fingerprint of each patient’s tumor.

Subject of Research: Ellagic acid as a chemosensitizer for oxaliplatin in wild-type TP53 colorectal cancer via the ATM/AMPK/HIPK2/Wip1 pathway

Article Title: Ellagic acid promoted efficacy of oxaliplatin on wild-type TP53 colorectal cancer via regulating ataxia-telangiectasia mutated protein kinase and Wip1

Article References: Zhao, Y., Ma, M., Han, S., Hu, J., Guo, X., Wang, W., Liu, S., Zhao, Z., Qiao, Y., & Wang, Y. (2026). Ellagic acid promoted efficacy of oxaliplatin on wild-type TP53 colorectal cancer via regulating ataxia-telangiectasia mutated protein kinase and Wip1. Frontiers in Pharmacology, 17, Article 1944826. https://doi.org/10.3389/fphar.2026.1944826

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1944826

Keywords: ellagic acid, oxaliplatin, colorectal cancer, ATM kinase, Wip1, p53, PPM1D, chemotherapy resistance, AMPK, HIPK2, patient-derived xenograft, polyphenols