A B S T R A C T
Biosensors inspired by biological sensory systems are valuable tools for detecting physiological and environmental
stimuli with high degrees of specificity and sensitivity. An itch irritant biosensor to detect environmental
changes or pruritogenic substances in human blood or tissues highly associated with inflammation and prevalent
conditions like atopic dermatitis (AD) has not been developed. To address this gap, we developed a novel bioelectronic
sensor by integrating the human itch receptor Mas-related G-protein-coupled receptor X2 (MRGPRX2)
with a graphene field-effect transistor (GFET). This MRGPRX2–GFET biosensor covalently immobilizes functional
receptors, enabling direct conversion of ligand-binding events into quantifiable electrical signals. We
demonstrate that the sensor can detect known MRGPRX2 agonists with exceptional sensitivity and specificity,
achieving a detection limit for SP at approximately 7 pM. Molecular dynamics (MD) simulations and mutational
effects reveal that ligand binding induces cytoplasmic conformational rearrangements in MRGPRX2, strengthening
receptor–graphene coupling and providing a mechanistic basis for signal transduction. Importantly, the
biosensor effectively distinguishes plasma samples from AD patients and healthy controls by capturing different
electrical signal responses. In our study, we establish a versatile platform for diagnosing and subtyping chronic itch disorders and offer a generalizable strategy for developing membrane receptor-based multiplexed “itch- print” biosensors.

2026.07.03

Abstract

Chronic itch, particularly in cholestatic and uremic conditions, poses
a notable clinical burden, yet treatment options remain inadequate.
MRGPRX4 (hX4), a bile-acid-sensing G-protein-coupled receptor
predominantly expressed in human sensory neurons, has emerged
as a critical mediator of cholestatic pruritus. Here we identified and
characterized HEP-50768, a potent and selective small-molecule inverse
agonist of hX4 through high-throughput screening and structure–activity
optimization. Structural elucidation through cryo-electron microscopy of
the hX4–inverse agonist complex structure revealed the unique binding
mode and inhibitory mechanism of HEP-50768. In hX4-humanized rats,
HEP-50768 robustly suppressed bile-acid-induced pruritic behaviors.
Comprehensive preclinical absorption, distribution, metabolism, excretion
and safety profiling was performed in both rats and monkeys, and these
findings establish HEP-50768 as a promising therapeutic candidate for
chronic itch, supporting its advancement to clinical evaluation.

Journal Club (2026.05.08)

Abstract
The Mas-related G protein-coupled receptor (MRGPR) X2 is expressed on skin mast cells
and can be stimulated by an unusually broad spectrum of ligands, including specific drugs
and even endogenous peptides. MRGPRX2 activation can induce mast cell degranulation
and consequently mediator release, leading to inflammatory and hypersensitivity reactions.
In addition, MRGPRX2 mediates pain and itching sensations, leading to increased efforts
to identify MRGPRX2 inhibitors, including plant-derived compounds. Components within
oat extracts have been shown to mediate anti-inflammatory and itch-relieving properties,
but a possible inhibitory effect on MRGPRX2 activation has not yet been investigated. We
aimed to fill this gap and explored whether an oat kernel extract can modulate MRGPRX2
activation. For this purpose, we established a mast cell model with the human LAD2
cell line and used it to investigate the consequences of exposure to oat extract. While
we did not observe any influence on cell viability, we analyzed the impact of oat extract
on MRGPRX2-mediated mast cell activation and degranulation initiated by the three
confirmed MRGPRX2 ligands c48/80, substance P, and cortistatin 14. Exposure to oat
extract resulted in a significant reduction in mast cell degranulation for all three ligands, as
assessed by the release of β-hexosaminidase, tryptase, cell surface expression of CD63 and
CD107a, and phosphorylation of ERK. All results were confirmed with primary human
mast cells. Thus, we demonstrated for the first time that oat extract leads to a significant
reduction in MRGPRX2 activation, pointing to a previously unrecognized capacity of
natural compounds to modulate this pathway.
Keywords: mast cells; MRGPRX2; oat extract