2. Academic Validation
  3. IMB16-5 alleviates liver fibrosis by targeting MICALL2/β-catenin signaling

IMB16-5 alleviates liver fibrosis by targeting MICALL2/β-catenin signaling

  • Int Immunopharmacol. 2026 Feb 1:170:116061. doi: 10.1016/j.intimp.2025.116061.
Mao-Xu Ge 1,  Dong Liu 2,  Ting-Chao Liu 3,  Zhen-Ning Lu 4,  Na Zhang 5,  Yi-Ming Li 5,  Si-Min Guo 5,  Yang Li 5,  Yi-Chen Liu 5,  Ju-Xian Wang 6,  Yi-Kang Shi 7,  Yu-Cheng Wang 8,  Hong-Wei He 9
Affiliations

Affiliations

  • 1 Department of Pharmacy, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: [email protected].
  • 2 School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
  • 3 National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao 266237, China.
  • 4 Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
  • 5 Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 6 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 7 National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology, NMPA Key Laboratory for Quality Research and Evaluation of Carbohydrate Based Medicine, Shandong University, Qingdao 266237, China. Electronic address: [email protected].
  • 8 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
  • 9 Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
PMID: 41461119 DOI: 10.1016/j.intimp.2025.116061
Abstract

Liver fibrosis, which is driven by activated hepatic stellate cells (HSCs), lacks approved therapies. Here, we identify MICAL-like protein 2 (MICALL2) as a novel therapeutic target and elucidate the antifibrotic mechanism of IMB16-5, a first-in-class arylsulfonylamino-benzanilide derivative. IMB16-5 significantly attenuated liver fibrosis in carbon tetrachloride (CCl₄)-injured mice by reducing Collagen deposition, inflammation, and HSC activation. Using limited proteolysis-small-molecule mapping (LiP-SMap) and molecular dynamics simulation, we discovered that IMB16-5 binds to the C-terminal domain of MICALL2. Mechanistically, MICALL2 prevents β-catenin from binding to GSK3β, thereby shielding β‑catenin from degradation and ultimately promoting Wnt signaling. IMB16-5 disrupts the MICALL2-β-catenin interaction, which suppresses β-catenin nuclear translocation. Consequently, IMB16-5 inhibits both glycolytic reprogramming and mitochondrial respiration in HSCs, promoting a quiescent phenotype. Further investigations revealed that HIF-1α acts downstream of the MICALL2/β-catenin signalingto integrate metabolic-inflammatory crosstalk. Critically, MICALL2 overexpression in vivo abolishes the therapeutic efficacy of IMB16-5, confirming target engagement. Our work establishes MICALL2 as a druggable target for liver fibrosis and identifies IMB16-5 as a promising therapeutic candidate that acts through dual metabolic suppression.

Keywords

Glycolytic reprogramming; Hepatic stellate cell; Inflammation; Liver fibrosis; MICALL2; β-catenin.

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