Ferulic acid promotes thrombopoiesis via TLR4/JAK2/STAT3 signaling: A novel therapeutic strategy for thrombocytopenia

Rui Liao; Miao Huang; Zhixuan Liu; Xinle Wang; Xiaolin Gan; Lu Hao; Peilian Jiang; Jiesi Luo; Qianqian Huang; Qibing Mei; Anguo Wu; Long Wang; Jianming Wu

doi:10.1016/j.bcp.2025.117088

Ferulic acid promotes thrombopoiesis via TLR4/JAK2/STAT3 signaling: A novel therapeutic strategy for thrombocytopenia

Biochem Pharmacol. 2025 Jun 24:239:117088. doi: 10.1016/j.bcp.2025.117088. Online ahead of print.

Authors

Rui Liao¹, Miao Huang², Zhixuan Liu³, Xinle Wang⁴, Xiaolin Gan³, Lu Hao⁴, Peilian Jiang³, Jiesi Luo⁴, Qianqian Huang³, Qibing Mei³, Anguo Wu⁵, Long Wang⁶, Jianming Wu⁷

Affiliations

¹ School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
² School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
³ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
⁴ School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China.
⁵ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China. Electronic address: wuanguo@swmu.edu.cn.
⁶ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China. Electronic address: wanglongsdu1226@swmu.edu.cn.
⁷ School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China; Sichuan Key Medical Laboratory of New Drug Discovery and Druggability, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China. Electronic address: jianmingwu@swmu.edu.cn.

PMID: 40571222
DOI: 10.1016/j.bcp.2025.117088

Abstract

Thrombocytopenia, a common hematological disorder, is associated with increased mortality in various diseases. However, the existing clinical treatments are often accompanied by various adverse effects and may even disrupt platelet homeostasis, highlighting the urgent need to develop novel therapeutic agents. Here, we developed a drug screening model based on virtual screening utilizing known monomeric components of Sanguisorba officinalis L. (SOL) and identified ferulic acid (FA) as a promising candidate for thrombocytopenia intervention. In vitro study using Meg-01 and K562 cell lines demonstrated that FA enhancedthe megakaryocyte (MK) maturation. In vivo, thrombopoietic effects were evaluated in Tg (itga2b:eGFP) transgenic zebrafish, revealing significant modulation of platelet production. Furthermore, in a thrombocytopenia mouse model, FA treatment increasedmegakaryocyte progenitors (MKPs) and MKs numbers in the bone marrow and spleen, inhibited oxidative stress and apoptosis in the bone marrow, and stimulated new platelet production in peripheral blood, thereby accelerating platelet count and function. Importantly, FA did not disrupt the platelet homeostasis in normal mice. Mechanistically, FA was identified as a direct activator of Toll-like receptor 4 (TLR4), which in turn activated the JAK2/STAT3 signaling pathway, thereby promoting MK differentiation and thrombopoiesis. These findings present FA as a potential novel therapeutic strategy for thrombocytopenia and provide a basis for its clinical development as an alternative or adjunctive therapy.

Keywords: Ferulic acid; Megakaryocyte differentiation; Platelet homeostasis; Sanguisorba officinalis L.; TLR4/JAK2/STAT3 signaling; Thrombocytopenia.