There are no FDA-approved medical therapies for NASH or liver fibrosis. There is an urgent need for new therapeutic approaches that are not only effective in ameliorating fat accumulation, cell death, and inflammation, but also is effective at reducing or reversing fibrosis. Galectin-3 protein, a member of a family of proteins which have the property of binding to terminal galactose residues in glycoproteins, has been implicated in the pathogenesis of liver fibrosis as well as in other organ fibrogenesis. Gal-3 null mice are resistant to liver fibrosis due to toxin administration, lung fibrosis due to bleomycin toxicity, and kidney fibrosis due to ureteral ligation. Therefore, gal-3 appears to play a critical role in parenchymal fibrogenesis. We have previously reported that GR-MD-02 and GM-CT-01, gal-3 inhibitors are able to reverse fibrosis and cirrhosis in rats rendered cirrhotic by treatment with thioacetamide. With TWS119 respect to NASH, the effect of gal-3 on the pathological process has given mixed results in experiments using gal-3 null mice. Iacobini, et al.have shown that in response to a high fat diet, normal mice readily developed fatty liver, inflammatory infiltrates, ballooning hepatocytes, and fibrosis, whereas the gal-3 null mice were resistant to the development of NASH and fibrosis. In contrast, Nomoto et al. found that gal-3 null mice at six months of age spontaneously developed pathological findings consistent with NASHand at 15 months there was evidence of neoplastic nodule formation. Moreover, using the cholinedeficient L-amino-acid-defineddiet model of NASH the same Tasocitinib authors found that steatosis and cellular necrosis were greater in the gal-3 null mice than in wild-type mice. Iacobini, et al. report following their gal-3 null mice for 24 months and did not find the effects reported by the other authors. There is no obvious explanation for the different findings of these two groups. In these studies, we used the same gal-3 inhibitors that showed a robust effect on thioacetamide-induced liver fibrosis in ratsto evaluate their effect in a murine model of NASH. Diabetic mice fed a high fat dietwere used to evaluate pharmacological inhibition of gal-3 using GR-MD-02 and GM-CT-01, two complex carbohydrate drugs that bind gal-3. Evaluation of the NASH model included histopathology evaluations of NASH, including hepatocellular fat accumulation, hepatocyte ballooning, intra-portal and intra-lobular inflammatory infiltrate, and deposition of collagen. In addition, the study evaluated the inflammatory mediator iNOS, the ALP/AGP scavenger receptor, and asmooth muscle actin, a marker for activated stellate cells. Treatment with GR-MD-02 significantly improved NASH activity and markedly reduced fibrosis in this mouse model of NASH. Similar effects were found with GM-CT-01, but with approximately 4-fold lower potency than GR-MD-02. The results suggest that these galectin targeting drugs may have potential in human disease. These experiments show that intravenous administration of the galectin-binding drug GR-MD-02 had reproducible efficacious effects in a murine model of steatohepatitis. Treatment reduced the NAFLD activity score which sums the characteristic histological findings of steatohepatitis including steatosis, hepatocyte ballooning, and inflammatory infiltrate. Moreover, treatment prevented accumulation of collagen and/or reduced accumulated collagen in the liver. The efficacy of treatment was unrelated to NASH progression as the positive effects were seen whether the drug was started early or late in the pathological process. The results of treatment efficacy were consistent between three separate experiments with different designs and dosing regimens.