2. Academic Validation
  3. LKB1 activated by NaB inhibits the IL-4/STAT6 axis and ameliorates renal fibrosis through the suppression of M2 macrophage polarization

LKB1 activated by NaB inhibits the IL-4/STAT6 axis and ameliorates renal fibrosis through the suppression of M2 macrophage polarization

  • Life Sci. 2025 Mar 15:370:123564. doi: 10.1016/j.lfs.2025.123564.
Weifei Liang 1,  Haoyu Wu 2,  Qishan Long 3,  Hong Lin 4,  Xiaoyu Lv 5,  Wen Ma 6,  Tao Wu 7,  Ai Li 8,  Qingyou Zheng 7,  Jinan Guo 9,  Xiangqiu Chen 10,  Jing Guo 11,  Donglin Sun 12
Affiliations

Affiliations

  • 1 Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China; Center for Cancer and Immunology Research, State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, 510180 Guangzhou, Guangdong, China.
  • 2 School of Public Health, Wenzhou Medical University, Wenzhou 325035, China; South Zhejiang Institute of Radiation Medicine and Nuclear Technology Application, Wenzhou 325809, China; Zhejiang Provincial Key Laboratory of Watershed Sciences and Health, Wenzhou Medical University, Wenzhou 325035, China.
  • 3 Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China.
  • 4 Department of Laboratory Medicine, Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, 511518 Qingyuan, Guangdong, China.
  • 5 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
  • 6 Clinical Laboratory, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China.
  • 7 Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China.
  • 8 Department of Clinical Medicine, The Second Clinical School of Guangzhou Medical University, Guangzhou 510000, China.
  • 9 Department of Urology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China. Electronic address: guo.jinan@szhospital.com.
  • 10 Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China. Electronic address: chxq0301@smu.edu.cn.
  • 11 Center of Oncology, Heyou Hospital, Shunde District, Foshan City 528306, Address:No. 1 of Heren Road, Junlan Community, Beijiao Town, Shunde District, Foshan City, Guangdong Province, China. Electronic address: guoj@stu.gzhmu.edu.cn.
  • 12 Department of Urology, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China. Electronic address: donglinsun@stu.gzhmu.edu.cn.
PMID: 40097066 DOI: 10.1016/j.lfs.2025.123564
Abstract

Background: Renal fibrosis is a critical pathological characteristic of chronic kidney disease, and current antifibrotic therapies has limited efficacy. Sodium butyrate (NaB) has been shown to be highly effective in mitigating bleomycin-induced pulmonary fibrosis; however, its specific impact on renal fibrosis and the underlying mechanisms remain unclear. This study aims to elucidate the role and mechanism of NaB in renal fibrosis by using a mouse model of renal fibrosis induced through Unilateral Ureteral Obstruction (UUO) and folic acid (FA) administration.

Results: NaB significantly decreased the distribution of collagen fibers in renal tissues and mitigated fibrosis in a dose-dependent manner. Further analysis indicated that NaB inhibited M2 macrophage polarization in the renal tissues of UUO model mice by blocking the phosphorylation of STAT6, hence reducing renal fibrosis. Additionally, in vitro experiments demonstrated that NaB inhibited fibroblast activation induced by M2 macrophages. Mechanistic studies revealed that NaB attenuates fibroblast activation and M2 macrophage polarization by upregulating LKB1 and inhibiting the activation of the STAT6 signaling pathway.

Conclusion: NaB may exert its effects by inhibiting the activation of the IL-4/STAT6 signaling pathway through the upregulation of LKB1, which suppress the polarization of M2 macrophages and consequently reduce renal fibrosis. These findings establish a theoretical foundation for NaB as a novel drug candidate for renal fibrosis and indicate its potential applicability in clinical treatments for this condition.

Keywords

IL-4/STAT6 signaling pathway; LKB1; M2 macrophage polarization; Renal fibrosis; Sodium butyrate (NaB).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10371
    98.40%, Pim1/AKK1/MST2/LKB1 Inhibitor
    Pim