Leszczynska Aleksandra, Alle Thibault, Kaufmann Benedikt, Sung Hana, Stoess Christian, Reca Agustina, Kim Andrea, Kim Sun, Tran Chelsea, Oukoloff Killian, Monti Ludovica, Lucero Bobby, Gertsman Ilya, Momper Jeremiah D, Hartmann Phillipp, Feldstein Ariel E, Dohil Ranjan, Ballatore Carlo
Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
ACS Pharmacol Transl Sci. 2025 Feb 24;8(3):885-898. doi: 10.1021/acsptsci.4c00738. eCollection 2025 Mar 14.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Oxidative stress is believed to play an important role in the development of MASH. Small aminothiol compounds such as cysteamine and its oxidized precursor, cystamine, are known pleiotropic compounds that exhibit relatively potent antioxidant and other effects. Herein, we evaluate the efficacy of cystamine, as well as two deuterated derivatives, in a choline-deficient, L-amino acid-defined, high-fat-diet (CDAA-HFD) mouse model of rapidly progressing liver fibrosis. Compared to control mice, daily oral administration of isotopically reinforced cystamine derivatives (200 mg/kg) led to a significant reduction of liver fibrosis and inflammation as well as oxidative stress. Moreover, the efficacy of treatment appeared to increase with the deuteration state of cystamine, with the tetradeuterated derivative, -cystamine, being the most effective. These results indicate that deuterated cystamine derivatives hold promise as potential candidates for the treatment of MASH.
代谢功能障碍相关脂肪性肝病（MASLD）是一种多因素慢性疾病，可进展为代谢功能障碍相关脂肪性肝炎（MASH）和肝纤维化，最终导致肝硬化和肝细胞癌。氧化应激被认为在MASH的发展中起重要作用。小氨基硫醇化合物如半胱胺及其氧化前体胱胺是已知的多效性化合物，具有相对较强的抗氧化和其他作用。在此，我们在快速进展性肝纤维化的胆碱缺乏、L-氨基酸限定、高脂饮食（CDAA-HFD）小鼠模型中评估了胱胺以及两种氘代衍生物的疗效。与对照小鼠相比，每日口服同位素强化的胱胺衍生物（200mg/kg）可显著降低肝纤维化、炎症以及氧化应激。此外，治疗效果似乎随着胱胺的氘代状态而增加，四氘代衍生物，即 -胱胺，最为有效。这些结果表明，氘代胱胺衍生物有望成为治疗MASH的潜在候选药物。
