Glycyrrhizic Acid Class Compounds in Immune Checkpoint Inhibitor Therapy: Stereochemistry, Mechanistic Hypotheses, and Protection Against Immune-Related Organ Injury
- 1Science and Innovation Center of Xinjiang Second Medical College, Karamay 834000, China
- 2School of Pharmacy, Xinjiang Second Medical College, Karamay 834000, China
Abstract
Glycyrrhizic acid class compounds are used empirically for checkpoint inhibitor-induced liver injury (ChILI), but their effects on antitumour efficacy remain uncertain. This narrative review examines isomer-specific pharmacology, clinical evidence and the candidate mechanisms proposed for this class, of which the high-mobility group box 1 (HMGB1) axis is the most developed. In a propensity-score-matched cohort of 229 patients, magnesium isoglycyrrhizinate (MgIG) plus corticosteroids was associated with higher day-10 alanine aminotransferase normalization than corticosteroids alone (30.7% versus 17.4%). A single-arm study of 67 patients reported study-defined liver injury in 9.0% during prophylaxis. Neither study reported antitumour efficacy or established causal clinical benefit. Modulating extracellular HMGB1 might reduce organ inflammation while altering tumor immunosuppression. However, neither direct HMGB1 engagement by MgIG nor a causal contribution of HMGB1 to ChILI was established in the identified literature. HMGB1 can also support antitumour immune priming; its net effect depends on redox state, tissue and timing. The corresponding 18α aglycone shows no measurable inhibition of 11β-hydroxysteroid dehydrogenase type 2 up to 20 µM in vitro, which does not establish clinical safety. Controlled trials should assess liver injury, corticosteroid exposure, antitumour outcomes and electrolyte safety together; routine prophylaxis is not supported.
Related
- Beyond structure prediction: Translating D‐I‐TASSER models into functional and mechanistic hypotheses
- Zamzam Water in Cancer and Beyond: Preclinical Cellular Effects and Proposed Mechanistic Hypotheses
- Rhizobial inoculation promotes glycyrrhizic acid production through jasmonic acid signaling in Glycyrrhiza uralensis
- THEOBROMA: an aggregated open database of 1.13 million natural products with per-compound license auditing, three-tier classification, and stereochemistry-aware deduplication
- False discovery rate control for grouped hypotheses: application to miRNAome data
BibTeX
@article{li2026glycyrrhizic,
title = {{Glycyrrhizic Acid Class Compounds in Immune Checkpoint Inhibitor Therapy: Stereochemistry, Mechanistic Hypotheses, and Protection Against Immune-Related Organ Injury}},
author = {Jie Li and Baojian Li and Ying Gao and Boshen Zhao and Jasur Kasim and Nanqi Shao and Zheng Gao and Zhan Liu and Zhongxing Song and Yinglai Yang and Jianguang Li},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219987},
url = {https://www.mdpi.com/1422-0067/27/21/9987},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Glycyrrhizic Acid Class Compounds in Immune Checkpoint Inhibitor Therapy: Stereochemistry, Mechanistic Hypotheses, and Protection Against Immune-Related Organ Injury
AU - Jie Li
AU - Baojian Li
AU - Ying Gao
AU - Boshen Zhao
AU - Jasur Kasim
AU - Nanqi Shao
AU - Zheng Gao
AU - Zhan Liu
AU - Zhongxing Song
AU - Yinglai Yang
AU - Jianguang Li
PY - 2026
DA - 2026/11/07
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219987
UR - https://www.mdpi.com/1422-0067/27/21/9987
AB - Glycyrrhizic acid class compounds are used empirically for checkpoint inhibitor-induced liver injury (ChILI), but their effects on antitumour efficacy remain uncertain. This narrative review examines isomer-specific pharmacology, clinical evidence and the candidate mechanisms proposed for this class, of which the high-mobility group box 1 (HMGB1) axis is the most developed. In a propensity-score-matched cohort of 229 patients, magnesium isoglycyrrhizinate (MgIG) plus corticosteroids was associated with higher day-10 alanine aminotransferase normalization than corticosteroids alone (30.7% versus 17.4%). A single-arm study of 67 patients reported study-defined liver injury in 9.0% during prophylaxis. Neither study reported antitumour efficacy or established causal clinical benefit. Modulating extracellular HMGB1 might reduce organ inflammation while altering tumor immunosuppression. However, neither direct HMGB1 engagement by MgIG nor a causal contribution of HMGB1 to ChILI was established in the identified literature. HMGB1 can also support antitumour immune priming; its net effect depends on redox state, tissue and timing. The corresponding 18α aglycone shows no measurable inhibition of 11β-hydroxysteroid dehydrogenase type 2 up to 20 µM in vitro, which does not establish clinical safety. Controlled trials should assess liver injury, corticosteroid exposure, antitumour outcomes and electrolyte safety together; routine prophylaxis is not supported.
SN - 1422-0067
ER -