Liver cancer remains one of the deadliest malignancies worldwide. According to the GLOBOCAN 2022 statistics released by the International Agency for Research on Cancer (IARC), about 860,000 new cases of liver cancer are diagnosed globally each year, ranking sixth in cancer incidence, and approximately 750,000 patients die of the disease, ranking third in cancer mortality. In China, liver cancer ranks fourth in incidence and second in mortality among digestive-system malignancies, making safer and more accessible intervention strategies an urgent need.
Huangjing (Polygonati Rhizoma), the dried rhizome of Polygonatum species, is a classic tonic herb in traditional Chinese medicine, first recorded in the ancient pharmacopoeia Ming Yi Bie Lu. A representative theory of traditional herbal processing holds that "vinegar processing guides the herb into the liver," a practice believed to enhance efficacy and reduce toxicity. The preparation studied here, Polygonatum vinegar, is brewed from Polygonatum that has undergone nine cycles of steaming and sun-drying, together with local sorghum, using the time-honored "steaming, fermenting, smoking, dripping and aging" craft of Shanxi aged vinegar, a national intangible cultural heritage. During solid state fermentation, acetic acid bacteria, lactic acid bacteria and yeasts work together to transform the herb's active components.
A research team led by Professor Changwu Yue from Yan'an Medical College, Yan'an University, together with Dr. Xiujuan Gu from Yan'an University Affiliated Hospital, has now provided systematic experimental evidence that this traditional fermented preparation acts against liver cancer. Their study was published online on June 2, 2026, in Acta Microbiologica Sinica (2026, 66(11): 5834–5852).
"Fermentation is far more than preservation. Microbial metabolism reshapes the chemical profile of the herb," said Professor Yue, corresponding author of the paper. "We wanted to test whether the ancient vinegar-processing theory could be explained with modern molecular and microbiological evidence."
The team first applied network pharmacology, a "multicomponent, multitarget, multipathway" approach. Integrating five databases, they identified 3,665 liver-cancer-related targets, of which 50 overlapped with the predicted targets of Polygonatum's active components. The top core targets, including TP53, PPARG, ESR1, TGFB1 and AKT1, were significantly enriched in 20 signaling pathways, including the p53 signaling pathway and cancer- and inflammation-related pathways.
Cell experiments confirmed the computational predictions. Polygonatum vinegar dose-dependently inhibited the proliferation and colony formation of human liver cancer cells (MHCC97H and HepG2) and mouse liver cancer cells (Hepa1-6), while its effect on normal human THLE2 hepatocytes was markedly weaker. Mechanistically, the vinegar raised intracellular reactive oxygen species (ROS), collapsed the mitochondrial membrane potential, upregulated the tumor suppressor genes TP53 and ESR1, and downregulated the pro-inflammatory factor TNF-α, pointing to a ROS-mediated mitochondrial apoptosis pathway that pushes cancer cells toward programmed death.
In C57BL/6 mice bearing subcutaneous liver tumors, orally administered Polygonatum vinegar slowed tumor growth in a dose-dependent manner. At the highest tested dose, it reduced tumor weight by 83.7% and tumor volume by 95.0%, while histopathological examination showed no obvious damage to the liver, spleen or kidney. Metagenomic and untargeted metabolomic analyses further revealed that the treatment reshaped the gut microbiota of the tumor-bearing mice, decreasing Bacteroides and increasing Akkermansia (a bacterium known to strengthen the gut barrier and antitumor immunity), and modulated bile acid, lipid and energy metabolism along the gut liver axis.
"Our findings connect three pieces of the puzzle: microbial transformation of the herb during fermentation, mitochondrial dysfunction in cancer cells, and remodeling of the gut microbiota," said Yue. "The next steps are to identify the key active substances through systematic chemical profiling, complete the evidence chain of the mitochondrial apoptosis pathway, and evaluate the overall safety in depth. Ultimately, we hope this work provides a scientific basis for the modern development of traditional fermented medicinal preparations."
Other contributors include Bingyan Lu, Yan Zhao, Sixin Chen and Axi Wang from Yan'an University and Yan'an Hospital of Traditional Chinese Medicine.
This work was supported by the Yan'an Science and Technology Bureau Project (2025-SFGG-080) and the National College Students Innovation Training Program (202310719044).
ACTA MICROBIOLOGICA SINICA
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