Mushroom Compound Pachymic Acid Supercharges Lenvatinib Against Liver Cancer by Starving Tumors of Sugar

Liver cancer remains one of the most formidable challenges in oncology, and hepatocellular carcinoma, the most common primary liver malignancy, continues to claim hundreds of thousands of lives each year worldwide. For patients with advanced disease, lenvatinib has become a cornerstone first-line therapy, a multi-kinase inhibitor that attacks tumor blood vessel formation and several cancer-driving signaling pathways at once. Yet even this powerful drug has an Achilles heel: with prolonged use, tumors frequently develop resistance, and the therapeutic benefit fades. Now, a team of researchers in China reports that a natural compound derived from a traditional medicinal mushroom may help break through that barrier, and their findings point to an unexpected metabolic mechanism at the heart of the synergy.

The new study, published in the journal Medical Oncology, comes from a group led by Zhiwei Wang and Peiyao Wu of the Affiliated Hospital of Nanjing University of Chinese Medicine, working with colleagues at Jiangsu Province Hospital of Chinese Medicine and the Children’s Hospital of Nanjing Medical University. Their focus was pachymic acid, a lanostane-type triterpenoid extracted from Poria cocos, a fungus long used in traditional Chinese medicine and increasingly scrutinized by modern pharmacologists for its anti-inflammatory, antifibrotic, and anticancer properties. Previous work had already hinted that pachymic acid could suppress the growth and metastatic potential of liver cancer cells in laboratory dishes, but the question of whether it could meaningfully strengthen a frontline targeted therapy like lenvatinib had remained open.

To answer it, the researchers turned to two widely used hepatocellular carcinoma cell lines, HepG2 and LM3, exposing them to pachymic acid, lenvatinib, or the two drugs in combination. They then measured a battery of malignant behaviors: how fast the cells multiplied, how readily they migrated and invaded, and how many underwent programmed cell death. The results were striking. In HepG2 cells, treatment with 20 micromoles per liter of pachymic acid dramatically increased the apoptosis rate from 8.5 percent to 15.2 percent, a difference the authors report as highly statistically significant. The same treatment cut the wound healing rate, a proxy for cell migration, from 59.3 percent down to 31.0 percent, indicating that the treated cells lost much of their ability to close gaps and spread across a surface.

But the most intriguing part of the story lies in metabolism rather than in cell death or motility. Cancer cells are famous for a metabolic quirk known as the Warburg effect, or aerobic glycolysis: even when oxygen is plentiful, they prefer to burn glucose through the inefficient glycolytic pathway rather than through mitochondrial respiration, converting sugar into lactate at a furious pace. This metabolic reprogramming supplies rapidly dividing tumors with the building blocks they need for new cells and helps them survive in the harsh, oxygen-poor interiors of growing masses. The researchers measured glucose consumption and lactate production in their cultures and found that pachymic acid sharply curtailed both. Glucose consumption in HepG2 cells fell from 5.3 micromoles per liter to 3.4 micromoles per liter, while lactate production dropped from 0.7 micromoles per liter to 0.3 micromoles per liter, with similar results in the LM3 line. In effect, the compound appeared to be pulling the plug on the tumor’s sugar-hungry engine.

The molecular culprit behind this metabolic shutdown, the team concluded, is peroxisome proliferator-activated receptor gamma, or PPARγ, a nuclear receptor best known for regulating fat metabolism and insulin sensitivity but increasingly implicated in cancer biology. By intervening through PPARγ, pachymic acid appears to disrupt the glycolytic program that hepatocellular carcinoma cells depend on, downregulating the expression of glycolysis-related proteins that keep the sugar pipeline flowing. This finding places the study within a growing body of literature linking PPARγ modulation to tumor metabolism. Other groups have shown, for example, that simvastatin can resensitize liver cancer cells to the related drug sorafenib by inhibiting a HIF-1alpha/PPARγ/PKM2-mediated glycolytic axis, and that melatonin suppresses bladder tumor formation by blocking PPARγ/ENO1-driven glycolysis. The Nanjing study extends this metabolic logic to lenvatinib, the current first-line standard for many patients with unresectable disease.

The synergy experiments are where the results become genuinely exciting. When the researchers combined pachymic acid with lenvatinib in vitro, cell survival in the treated cultures dropped from 53.3 percent with lenvatinib alone to 33.3 percent with the combination, a difference that reached the stringent threshold of p less than 0.001. In other words, adding the mushroom-derived compound made the targeted therapy substantially more lethal to the cancer cells than either agent’s individual contribution would predict, a hallmark of true pharmacological synergy rather than simple additivity. The combination did not merely slow proliferation; it pushed cells toward apoptosis while simultaneously starving them of the metabolic fuel that supports invasion and spread.

Critically, the team did not stop at the culture dish. To verify that the effect would hold in a living organism, they conducted tumor-bearing experiments in nude mice, immunodeficient animals that accept human tumor grafts and are a standard preclinical model for cancer drug testing. The in vivo results mirrored the laboratory findings. Tumors in animals treated with lenvatinib alone reached an average volume of 483.0 cubic millimeters, while those receiving the pachymic acid plus lenvatinib combination measured only 357.5 cubic millimeters, a statistically significant reduction. The animal work, which was approved by the institutional animal ethics committee before initiation, provides an important bridge between cell culture observations and the possibility of clinical translation, though the authors and outside observers alike will note that mouse models are an early and imperfect step on the long road to human trials.

The context surrounding lenvatinib resistance gives these findings particular urgency. Recent research has illuminated several mechanisms by which hepatocellular carcinoma evades the drug, including the release of vascular endothelial growth factor from resistant cells that promotes malignant behavior through tumor-associated macrophages, and p62 aggregation-mediated mitochondrial mitophagy triggered by c-Myc overexpression in resistance to related kinase inhibitors. Metabolic reprogramming has emerged as a recurring theme in this resistance landscape. A 2023 study showed that targeting ACYP1-mediated glycolysis could reverse lenvatinib resistance and restrict tumor progression, and a 2025 report found that ponicidin, another plant-derived compound, promotes ferroptosis to enhance treatment sensitivity in lenvatinib-resistant cells through regulation of the KEAP1/NRF2 pathway. The new work adds PPARγ-driven glycolysis to this map and suggests that pachymic acid could slot into a broader strategy of combining targeted therapies with metabolic interventions.

The study also contributes to a renaissance of interest in traditional Chinese medicine compounds as sources of scientifically validated anticancer agents. A 2025 review in Molecular Cancer argued that traditional Chinese medicine can be tailored for cancer therapy in rigorous, mechanism-driven ways, and the pachymic acid study exemplifies this approach: rather than testing an uncharacterized herbal mixture, the researchers isolated a defined molecule, identified a specific molecular target, quantified metabolic endpoints, and validated the combination in vivo. Poria cocos itself has been the subject of a recent comprehensive review of its antitumor activity and its potential as an adjuvant in chemotherapy, and pachymic acid has separately shown protective effects in models of pulmonary fibrosis, cardiac ischemia-reperfusion injury, and pancreatic fibrosis, hinting at a versatile pharmacology that extends well beyond oncology.

Of course, substantial caveats remain before patients could benefit. The concentrations used in the cell experiments, 20 micromoles per liter, must be reconciled with achievable drug levels in human plasma, and the safety, pharmacokinetics, and optimal dosing of pachymic acid in combination regimens are unknown. The researchers report no competing interests and note that the study was funded by the Outstanding Young Doctor Training Program of Jiangsu Province Hospital of Chinese Medicine and internal hospital programs, and they state that data will be made available on request. Still, the core message is compelling: a compound from a mushroom used for centuries in East Asian medicine can, by flipping a metabolic switch through PPARγ, make one of modern hepatology’s most important drugs work harder. As hepatocellular carcinoma continues to resist single-agent approaches, the marriage of ancient natural products with contemporary targeted therapy may prove to be one of the more surprising and productive alliances in cancer research.

Subject of Research: Synergistic antitumor effects of pachymic acid and lenvatinib in hepatocellular carcinoma via PPARγ-mediated inhibition of aerobic glycolysis

Article Title: Pachymic acid exhibits synergistic antitumor efficacy with lenvatinib in hepatocellular carcinoma by targeting PPARγ to inhibit glycolysis

Article References: Wang, Z., Wu, P., Zhang, C., Zhang, T., Gu, C., Xie, X., Feng, X., Zhou, Q., & Jiang, Z. (2026). Pachymic acid exhibits synergistic antitumor efficacy with lenvatinib in hepatocellular carcinoma by targeting PPARγ to inhibit glycolysis. Medical Oncology, 43(10), Article 271. https://doi.org/10.1007/s12032-026-03398-0

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03398-0

Keywords: hepatocellular carcinoma, pachymic acid, lenvatinib, PPARγ, aerobic glycolysis, drug resistance, cancer metabolism, Poria cocos, targeted therapy, combination therapy, traditional Chinese medicine, preclinical study