Discovery of scutellarin as a MRGX2 agonist via MRGX2/CMC strategy and revelation of its pseudo-allergic mechanism
Abstract
BackgroundShu-Gan-Ning injection (SGN) is widely used clinically to treat hepatopathy, improve liver function, and enhance immunity. However, pseudo-allergic reactions (PARs) occur after administration and the causative compounds remain unclear. Therefore, it is of paramount importance to pinpoint the “culprit” compound in SGN and explore its underling mechanism.MethodsMas-related G protein-coupled receptor X2 cell membrane chromatography (MRGX2/CMC)-HPLC-MS was established and used to “capture” and identify risk components in SGN. The interactions between risk components and MRGX2 were investigated by integrating MRGX2/CMC detection, virtual docking, and frontal analysis assays. MRGX2-knockdown LAD2 cell models were used to verify the specific target of the risk components and the signaling pathways that trigger PARs. C57BL/6 mice were used to evaluate the PARs induced by hazardous compounds. The conditional knockout mice model was used to evaluate the key role of MAS-related G protein-coupled receptor, member B2 (MRGB2) in mast cells in vivo pseudo-allergic reaction induced by target compound.ResultsWe identified scutellarin, baicalin, and oroxyloside as MRGX2‐binding components in SGN. Affinity analysis revealed KD values of 2.69 × 10−7 M for scutellarin, 2.18 × 10−7 M for baicalin, and 7.21 × 10−7 M for oroxyloside. Functional assays showed that only scutellarin (5–100 μM) concentration-dependently induced mast cell degranulation, Ca2+ influx, and release of inflammatory mediators. MRGX2 knockdown (mRNA ∼50%, protein ∼70%) significantly attenuated these responses, and pathway analysis confirmed that scutellarin activates the PLCγ/PKC cascade via MRGX2. In vivo, scutellarin induced local paw swelling and Evans blue extravasation, as well as systemic hypothermia, with EC50 values of 0.92 mg/kg for temperature reduction and 1.82 mg/kg for Evans blue exudation. In mast cell‐specific Mrgb2 conditional knockout (CKO) mice, scutellarin‐induced paw swelling and Evans blue leakage were significantly reduced compared with wild‐type mice, confirming the critical role of MRGB2 in mediating the pseudo‐allergic response.DiscussionCollectively, these findings identify scutellarin as an MRGX2 agonist and a pseudo‐allergic risk compound in SGN, highlighting the need for quality control measures for scutellarin in baicalin‐containing preparations.
Related
- Targeting Endoplasmic Reticulum Stress with Tauroursodeoxycholic Acid: A Potential Therapeutic Strategy for Allergic Airway Diseases
- Exploring the mechanism of 6PPD/6PPD-Q-induced allergic rhinitis based on network toxicology, molecular docking, and molecular dynamic simulation
- Direct-to-Biology Strategy Accelerates CRBN-Targeting Molecular Glue Degrader Discovery
- Integrated NMR, HPLC-Chemometrics, and Network Pharmacology Strategy for Quality Assessment and Mechanism Elucidation of Gelatinous Chinese Medicines
- From prognostic modeling to drug discovery: a metabolism-guided strategy for herbal small-molecule screening in gastric cancer
BibTeX
@article{he2026discovery,
title = {{Discovery of scutellarin as a MRGX2 agonist via MRGX2/CMC strategy and revelation of its pseudo-allergic mechanism}},
author = {Feng He and Haoyun Bai and Quan Zhang and Wenhao Chen and Yu He and Jing Li and Shengyu Zhou and Shen Yang and Jinjin Wang and Yanyan Zhang and Yanni Lv and Shengli Han},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1898140},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1898140},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Discovery of scutellarin as a MRGX2 agonist via MRGX2/CMC strategy and revelation of its pseudo-allergic mechanism
AU - Feng He
AU - Haoyun Bai
AU - Quan Zhang
AU - Wenhao Chen
AU - Yu He
AU - Jing Li
AU - Shengyu Zhou
AU - Shen Yang
AU - Jinjin Wang
AU - Yanyan Zhang
AU - Yanni Lv
AU - Shengli Han
PY - 2026
DA - 2026/11/02
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1898140
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1898140
AB - BackgroundShu-Gan-Ning injection (SGN) is widely used clinically to treat hepatopathy, improve liver function, and enhance immunity. However, pseudo-allergic reactions (PARs) occur after administration and the causative compounds remain unclear. Therefore, it is of paramount importance to pinpoint the “culprit” compound in SGN and explore its underling mechanism.MethodsMas-related G protein-coupled receptor X2 cell membrane chromatography (MRGX2/CMC)-HPLC-MS was established and used to “capture” and identify risk components in SGN. The interactions between risk components and MRGX2 were investigated by integrating MRGX2/CMC detection, virtual docking, and frontal analysis assays. MRGX2-knockdown LAD2 cell models were used to verify the specific target of the risk components and the signaling pathways that trigger PARs. C57BL/6 mice were used to evaluate the PARs induced by hazardous compounds. The conditional knockout mice model was used to evaluate the key role of MAS-related G protein-coupled receptor, member B2 (MRGB2) in mast cells in vivo pseudo-allergic reaction induced by target compound.ResultsWe identified scutellarin, baicalin, and oroxyloside as MRGX2‐binding components in SGN. Affinity analysis revealed KD values of 2.69 × 10−7 M for scutellarin, 2.18 × 10−7 M for baicalin, and 7.21 × 10−7 M for oroxyloside. Functional assays showed that only scutellarin (5–100 μM) concentration-dependently induced mast cell degranulation, Ca2+ influx, and release of inflammatory mediators. MRGX2 knockdown (mRNA ∼50%, protein ∼70%) significantly attenuated these responses, and pathway analysis confirmed that scutellarin activates the PLCγ/PKC cascade via MRGX2. In vivo, scutellarin induced local paw swelling and Evans blue extravasation, as well as systemic hypothermia, with EC50 values of 0.92 mg/kg for temperature reduction and 1.82 mg/kg for Evans blue exudation. In mast cell‐specific Mrgb2 conditional knockout (CKO) mice, scutellarin‐induced paw swelling and Evans blue leakage were significantly reduced compared with wild‐type mice, confirming the critical role of MRGB2 in mediating the pseudo‐allergic response.DiscussionCollectively, these findings identify scutellarin as an MRGX2 agonist and a pseudo‐allergic risk compound in SGN, highlighting the need for quality control measures for scutellarin in baicalin‐containing preparations.
SN - 1663-9812
ER -