Lingonberry Extract Starves Oral Cancer Cells by Rewiring Their Energy Metabolism

A humble northern berry, long a staple of Scandinavian forests and breakfast jams, is now at the center of a laboratory investigation into one of the most stubborn cancers of the head and neck. Researchers at the University of Helsinki, working with colleagues at the University of Eastern Finland, the University of Oulu, and partner institutions, report that a cold-pressed extract of lingonberry (Vaccinium vitis-idaea) can suppress the growth and spread of oral squamous cell carcinoma cells in culture while leaving normal oral fibroblasts largely untouched. The study, published in BMC Complementary Medicine and Therapies, points to an intriguing mechanism: the extract appears to interfere with the distinctive way cancer cells generate and spend their energy.

Oral squamous cell carcinoma, abbreviated OSCC, is the most common malignancy of the oral cavity and remains a formidable clinical challenge. Despite advances in surgery, radiation, and chemotherapy, five-year survival rates have improved only modestly over recent decades, and tumors frequently invade surrounding tissue and spread to cervical lymph nodes before they are detected. This grim picture has driven researchers to look for preventive strategies and complementary agents that could slow the progression of premalignant lesions or restrain invasive behavior. Berry polyphenols, a broad family of plant secondary metabolites that includes anthocyanins, flavonols, and phenolic acids, have repeatedly shown anticancer activity in preclinical models, making them attractive candidates for such approaches.

The Finnish team, led by first author Tuulia Onali together with senior author Tuula Salo and their collaborators, prepared their test material by cold-pressing lingonberries, a gentle processing method that avoids heat degradation of delicate phytochemicals. The resulting extract was characterized for its total phenolic content and total anthocyanin content, and the researchers confirmed its antioxidant capacity using standard assays. To distinguish the biochemical activity of the polyphenols from the simple effect of acidity, the team prepared two versions of the extract: one in its native, acidic state and another with its pH adjusted to match the surrounding culture medium. This pH-matched control proved crucial for interpreting which effects were attributable to the berry compounds themselves rather than to low pH.

The experimental design was deliberately broad. Four different human oral cell types were exposed to the extract at concentrations of 0.1 percent, 1 percent, and 2 percent in the culture medium. Two of these were malignant: SCC-25, a cell line derived from a primary squamous cell carcinoma of the oral tongue, and HSC-3, a cell line established from a lymph node metastasis of an oral tongue carcinoma, representing the invasive stage of the disease. The third was IHGK, a line of oral keratinocytes immortalized by the human papillomavirus type 16, which models the early, premalignant transformation of oral epithelium. The fourth, and arguably the most important, was a culture of normal oral fibroblasts, or NOF, which served as the healthy-tissue benchmark. Any candidate preventive agent must, after all, harm cancer cells without damaging the surrounding normal tissue.

After 72 hours of treatment, the results were striking in their selectivity. Both the native and the pH-adjusted lingonberry extracts inhibited the proliferation of the two OSCC cell lines, but the normal oral fibroblasts continued to grow essentially unaffected. The HPV-immortalized keratinocytes, sitting in the gray zone between normal and malignant, were significantly inhibited only by the native extract, suggesting that the acidity of the unadjusted preparation contributed to its effect on these premalignant cells. Live-cell imaging over 48 hours allowed the researchers to watch proliferation and cell death unfold in real time, and it revealed an additional nuance: the pH-adjusted extract increased apoptosis, the controlled program of cell suicide, in the metastatic HSC-3 cells, indicating that the berry compounds can actively push invasive cancer cells toward self-destruction rather than merely slowing their division.

Invasion, the property that makes OSCC so dangerous clinically, was examined in a three-dimensional spheroid model. HSC-3 cells were grown as compact spherical clusters and embedded in a matrix that mimics the tissue surrounding a tumor, allowing the researchers to measure how far the cells burrow outward over 72 hours. Both the native and the pH-adjusted extracts reduced invasion to a similar degree. This convergence is significant because it suggests that the anti-invasive effect is a genuine property of the berry phytochemicals rather than an artifact of acidity, which can itself influence cell behavior in culture.

The most novel part of the study, however, lies in its exploration of cellular energy metabolism. Cancer cells famously rewire their bioenergetics: even in the presence of abundant oxygen, many tumors prefer glycolysis, the fermentation of glucose to lactate, over the more efficient mitochondrial oxidation of nutrients. This phenomenon, known as the Warburg effect, supplies rapidly dividing cells with biosynthetic building blocks and supports their relentless proliferation. Because transformed and normal cells differ in these metabolic pathways, energy metabolism represents a potential Achilles’ heel that a dietary compound might exploit selectively.

To probe this vulnerability, the researchers measured glycolysis and mitochondrial respiration in all four cell lines after 48 hours of pretreatment with the extracts, using established respirometry techniques that quantify oxygen consumption and extracellular acidification. The findings were asymmetric in a way that favors therapeutic selectivity. Both extract preparations inhibited glycolysis in the malignant OSCC cells, throttling the fermentative pathway on which those cells depend, while exerting no measurable effect on glycolysis in the normal fibroblasts. Mitochondrial respiration responded in opposite directions depending on the cell type: the extract increased respiration in the malignant cells, perhaps forcing them to compensate for the glycolytic blockade by shifting toward oxidative phosphorylation, whereas it decreased respiration in the immortalized keratinocytes and the normal fibroblasts. The authors propose that lingonberry extract inhibits proliferation and invasion of OSCC, at least in part, by targeting this differential energy metabolism of transformed cells.

The implications, if the findings translate beyond the laboratory, are twofold. First, lingonberry phytochemicals could contribute to prevention, either by slowing the progression of premalignant oral lesions or by reducing the risk of transformation in high-risk epithelium. Second, the extract’s ability to curb invasion suggests a potential role in restraining tumor progression after diagnosis, potentially complementing conventional therapy. The researchers themselves frame the results as evidence that lingonberry could have significance in both the prevention and the inhibition of progression of oral carcinoma. It is worth emphasizing the caveats that temper such enthusiasm: these experiments were conducted in cell culture, at extract concentrations that would need careful translation into achievable dietary or pharmacological exposure, and without the immune system, vasculature, and tissue architecture of a living patient. The work was supported by the Sigrid Jusélius Foundation, the Minerva Foundation, the University of Helsinki, and Helsinki University Hospital, and an abstract of the findings was previously presented at the European Association for Cancer Research congress in 2025.

Nevertheless, the study adds a compelling entry to the growing catalog of evidence that common foods contain molecules with genuinely selective anticancer activity. The lingonberry, tart and abundant across the boreal forests of northern Europe, is rich in anthocyanins and phenolic acids whose individual contributions the team has begun to dissect through chromatographic characterization. What makes this work stand out is not merely the observation that a berry extract kills cancer cells in a dish, a result reported many times before with many plants, but the demonstration of selectivity on two fronts: malignant cells were suppressed while normal fibroblasts were spared, and the metabolic fingerprint of that suppression, reduced glycolysis paired with altered respiration, matches the theoretical profile of a compound that exploits the Warburg effect. The next steps, which the field will watch closely, involve identifying the specific polyphenols responsible, validating the effects in animal models of oral carcinogenesis, and ultimately determining whether regular consumption or concentrated preparations of lingonberry can influence the course of oral lesions in humans. For now, the tart red berry of the northern woods has earned a place in the serious conversation about cancer metabolism and prevention.

Subject of Research: Anticancer effects of lingonberry extract on oral squamous cell carcinoma cell metabolism

Article Title: Cold-pressed lingonberry (Vaccinium vitis-idaea) extract inhibits proliferation and invasion of oral carcinoma cells and modulates cellular energy metabolism

Article References: Onali, T., Korelin, K., Al-Samadi, A., Kivimäki, A., Halahlah, A., Wahbi, W., Eriksson, O., Korpela, R., & Salo, T. (2026). Cold-pressed lingonberry (Vaccinium vitis-idaea) extract inhibits proliferation and invasion of oral carcinoma cells and modulates cellular energy metabolism. BMC Complementary Medicine and Therapies. https://doi.org/10.1186/s12906-026-05548-3

Image Credits: AI Generated

DOI: 10.1186/s12906-026-05548-3

Keywords: lingonberry, oral squamous cell carcinoma, polyphenols, glycolysis, mitochondrial respiration, apoptosis, cancer metabolism, invasion, proliferation, natural products, cancer prevention, head and neck cancer