Zhilining formula alleviates ulcerative colitis by restricting STAT3 activation and subsequent Th17 cell...

Area of Science:

• Pharmacology
• Immunology
• Traditional Chinese Medicine

Background:

• Ulcerative colitis (UC) is a chronic inflammatory bowel disease with increasing prevalence and limited treatment options.
• Zhilining Formula (ZLN), a Traditional Chinese Medicine (TCM), demonstrates clinical effectiveness in UC, but its active components and mechanisms are not fully understood.

Purpose of the Study:

• To identify the bioactive compounds and molecular targets of ZLN.
• To elucidate the pharmacological mechanisms behind ZLN's anti-UC effects, focusing on its impact on immune pathways.

Main Methods:

• Utilized network pharmacology, machine learning, and Mendelian randomization to identify ZLN's core targets and pathways in UC.
• Employed animal models (DSS and TNBS-induced colitis), IL-17A neutralization, and AAV9-Stat3 to validate the role of Th17 cell differentiation and STAT3 signaling.
• Characterized ZLN's chemical composition using UHPLC-MS/MS and confirmed direct compound-target interactions via surface plasmon resonance.

Main Results:

• ZLN significantly ameliorated colitis symptoms in animal models.
• Identified 275 overlapping targets mediating ZLN's effects, with Th17 cell differentiation highlighted as a central pathway.
• Confirmed that ZLN inhibits Th17 cell differentiation by blocking STAT3 activation, with key compounds directly binding to STAT3.

Conclusions:

• Zhilining Formula (ZLN) effectively treats ulcerative colitis (UC) by suppressing Th17 cell differentiation through STAT3 inhibition.
• These findings validate ZLN's clinical use and propose targeting the STAT3-Th17 axis as a novel therapeutic strategy for UC using TCM principles.