Peking University, October 30, 2024:
Addressing the challenge of cholestatic itch, the scientific community has been pursuing innovative solutions. Recently, researchers from Peking University, led by Professor Lei Xiaoguang, in collaboration with Professor Li Yulong and Professor Chen Yu (Beijing You'an Hospital), uncovered how bile acids activate hX4 to induce cholestatic itch. This work promotes a new treatment strategy for liver disease that avoids itch side effects. Their findings, entitled “Structure-guided discovery of bile acid derivatives for treating liver diseases without causing itch,” were published in Cell on October 29, 2024.

Why it matters:
Bile acids play a crucial physiological role in the body, primarily in fat digestion and cholesterol regulation. Bile acids are continuously recycled via the enterohepatic circulation to maintain metabolic balance as the liver's final product of cholesterol metabolism. When bile flow is obstructed, leading to cholestasis, bile acids accumulate due to disrupted metabolism. Up to 80% of cholestasis patients experience severe itching (pruritus), significantly impacting their quality of life. However, the molecular mechanisms underlying cholestatic pruritus remain unclear, and effective therapeutic options are lacking.

Methodology:
The research teams utilized LC/MS-MS technology to analyze bile acid components in the plasma of cholestasis patients with or without itch symptoms. Additionally, the teams employed cryo-EM to reveal the mechanism of bile acids activating MRGPRX4 (hX4). In addition to investigating bile acids and pruritus mechanisms, the researchers also examined the mechanism behind the itching side effects associated with the clinical drug obeticholic acid (OCA). They identified OCA’s target linked to itch at the cellular level and validated this mechanism in animal models and human subjects. Ultimately, using the structure and mechanistic insight, the teams designed a new compound that retains OCA’s therapeutic effect without causing the itch.

Key findings:
- This work identified that 3-sulfated bile acids accumulate in cholestatic patients, worsening itch symptoms.
- Using cryo-EM, the research teams solved the complex structure of hX4 bound to a bile acid analog DCA-3P (deoxycholic acid with a phosphate-modified 3-hydroxy group), revealing the crucial role of the 3-hydroxy group (3-OH) in hX4 activation.
- In this study, the researchers experimentally verified that the pruritus caused by OCA is also mediated through the activation of the hX4 receptor.
- Building on the bile acid activating hX4 mechanism, the researchers removed the 3-OH from OCA to create the derivative C7. Remarkably, C7 retained its efficacy in treating liver diseases while avoiding the side effects of itch.

This groundbreaking study opens up a new avenue for treating liver diseases, offering hope for more effective and comfortable therapeutic options for patients with cholestasis.

Written by: Yang Jun, Lei Xiaoguang
Edited by: Zhang Jiang
Source: College of Chemistry and Molecular Engineering, Peking University