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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Integrative and Regenerative Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1403943

Integrating Mendelian randomization and single-cell RNA sequencing to identify therapeutic targets of baicalin for type 2 diabetes mellitus

Provisionally accepted
Ying-Chao Liang Ying-Chao Liang 1Ling Li Ling Li 1Jia-Lin Liang Jia-Lin Liang 1De-Liang Liu De-Liang Liu 2*Shu-fang Chu Shu-fang Chu 2Hui-Lin Li Hui-Lin Li 2*
  • 1 The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, China
  • 2 Department of Endocrinology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China

The final, formatted version of the article will be published soon.

    Background: Alternative and complementary therapies play an imperative role in the clinical management of Type 2 diabetes mellitus (T2DM), and exploring and utilizing natural products from a genetic perspective may yield novel insights into the mechanisms and interventions of the disorder.To identify the therapeutic target of baicalin for T2DM, we conducted a Mendelian randomization study. Druggable targets of baicalin were obtained by integrating multiple databases, and target-associated cis-expression quantitative trait loci (cis-eQTL) originated from the eQTLGen consortium. Summary statistics for T2DM were derived from two independent genome-wide association studies available through the DIAGRAM Consortium (74,124 cases vs. 824,006 controls) and the FinnGen R9 repository (9,978 cases vs. 12,348 controls). Network construction and enrichment analysis were applied to the therapeutic targets of baicalin. Colocalization analysis was utilized to assess the potential for the therapeutic targets and T2DM to share causative genetic variations. Molecular docking was performed to validate the potency of baicalin. Single-cell RNA sequencing was employed to seek evidence of therapeutic targets' involvement in islet function.Results: Eight baicalin-related targets proved to be significant in the discovery and validation cohorts. Genetic evidence indicated the expression of ANPEP, BECN1, HNF1A, and ST6GAL1 increased the risk of T2DM, and the expression of PGF, RXRA, SREBF1, and USP7 decreased the risk of T2DM. In particular, SREBF1 has significant interaction properties with other therapeutic targets and is supported by strong colocalization. Baicalin had favorable combination activity with eight therapeutic targets. The expression patterns of the therapeutic targets were characterized in cellular clusters of pancreatic tissues that exhibited a pseudo-temporal dependence on islet cell formation and development.This study identified eight potential targets of baicalin for treating T2DM from a genetic perspective, contributing an innovative analytical framework for the development of natural products. We have offered fresh insights into the connections between therapeutic targets and islet cells. Further, fundamental experiments and clinical research are warranted to delve deeper into the molecular mechanisms of T2DM.

    Keywords: type 2 diabetes mellitus, Baicalin, Therapeutic target, Mendelian randomization, single-cell RNA sequencing

    Received: 20 Mar 2024; Accepted: 02 Jul 2024.

    Copyright: © 2024 Liang, Li, Liang, Liu, Chu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    De-Liang Liu, Department of Endocrinology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China
    Hui-Lin Li, Department of Endocrinology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, 518033, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.