Comparative efficacy of distinct Gal-3 inhibitors and a LOX inhibitor on Galectin-3-induced inflammation and fibrosis in <em>in vitro</em> MASH models — ASN Events
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  3. Comparative efficacy of distinct Gal-3 inhibitors and a LOX inhibitor on Galectin-3-induced inflammation and fibrosis in in vitro MASH models

Comparative efficacy of distinct Gal-3 inhibitors and a LOX inhibitor on Galectin-3-induced inflammation and fibrosis in in vitro MASH models (#325)

Youngho Son 1 2 , Hye-Eun Byeon 3 , Sung-E Choi 1 , Youngha Kim 1 2 , Jayoung Jeon 1 , Seung Jin Han 1 , Hae Jin Kim 1 , Kwan-Woo Lee 1 , NAMI LEE 1
  1. Endocrinology and Metabolism, Ajou University School of Medicine, Suwon, Republic of Korea
  2. Biomedical Sciences, Graduate School of Ajou University, Suwon, Republic of Korea
  3. Institute of Medical Science, Ajou University School of Medicine, Suwon, Republic of Korea

Aims: Metabolic dysfunction-associated steatohepatitis (MASH)-associated fibrosis is the primary driver of progression toward irreversible cirrhosis and liver failure (1,2). Due to its complex multi-pathway pathogenesis, direct antifibrotic therapies are still urgently needed (3). Because Galectin-3 plays a pivotal role in driving both hepatic inflammation and fibrogenesis, it represents a highly promising therapeutic target (4). Here, we aimed to compare the therapeutic efficacy of three distinct clinical candidates in mitigating Galectin-3-induced inflammation and fibrosis using established in vitro MASH models.

Methods: THP-1 monocytes were differentiated with PMA and activated with Galectin-3 to induce inflammation. LX-2 cells were stimulated with PA plus either Galectin-3 or TGF-β to induce fibrosis. The activated cells were treated with Olitigaltin (Gal-3 inhibitor), PXS-4787 (LOX inhibitor), or Selvigaltin (oral Gal-3 inhibitor) at concentrations of 0.1, 1, and 10 μM. The anti-inflammatory and antifibrotic efficacy of these agents was evaluated by measuring cytokine (TNF-α, IL-1β, IL-6) and fibrotic gene (COL1A1, α-SMA, TIMP2, CTGF) expression via qRT-PCR. Furthermore, fibrotic protein expression in LX-2 cells under both activation conditions was confirmed by Western blot.

Results: Treatment with all three therapeutic agents (Gal-3 inhibitors, LOX inhibitor) concentration-dependently attenuated the expression of pro-inflammatory cytokines in activated THP-1 macrophages and suppressed the mRNA expression of key fibrotic genes in activated LX-2 cells. At the protein level, all three candidates similarly downregulated profibrotic protein expression in PA+Gal-3-stimulated LX-2 cells in a dose-dependent manner, with comparable therapeutic efficacy consistently maintained under PA+TGF-β stimulation.

Conclusion: This study underscores that blocking Gal-3-mediated inflammatory and fibrotic cascades, either directly through Gal-3 inhibition or via LOX modulation, is highly effective in mitigating MASH progression. The robust, concentration-dependent efficacy of these three agents paves the way for novel monotherapies or synergy-driven combination strategies against advanced liver fibrosis.

  1. Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184(10):2537-2564.
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  3. Zhu Y, Cai B. Mechanisms and therapeutic insights into MASH-associated fibrosis. Trends Endocrinol Metab. 2025;37(5):402–417.
  4. Henderson NC, Mackinnon AC, Farnworth SL, et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci USA. 2006;103(13):5060-5065.