Unlocking therapeutic potential of amlexanox in MASH with insights into bile acid metabolism and microbiome.

npj Gut and Liver Pub Date : 2025-01-01 Epub Date: 2025-02-01 DOI:10.1038/s44355-024-00015-7
Wenjing You, Jianfei Ji, Danwan Wen, Chen Wang, Xiaoli Sun, Peng Zhao
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Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) has become a global health issue associated with obesity and diabetes. It is becoming a leading cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Despite its increasing prevalence, effective pharmacotherapies for MASH remain limited, underscoring the urgent need for novel interventions. Amlexanox, an inhibitor of noncanonical IκB kinases, has demonstrated potential in restoring insulin sensitivity and glucose homeostasis in obese mice and human patients, as shown in our earlier studies. Here, we aimed to assess the therapeutic potential of amlexanox in dyslipidemia-associated diseases, particularly MASH and HCC, and to elucidate the underlying mechanism. We employed GAN diet-fed Ldlr -/- mice, which simultaneously develop obesity, MASH, and atherosclerosis, to recapitulate human metabolic syndrome and associated complications. Amlexanox was administrated orally to these mice after disease onset to examine its therapeutic efficacy. Our study demonstrates that even a low dose of amlexanox significantly reversed MASH and nearly completely prevented the progression from MASH to HCC. Both phenotypic and transcriptomic studies revealed that amlexanox markedly improved MASH-related dyslipidemia, hepatic steatosis, inflammation, liver injury, and hepatic fibrosis. Furthermore, multi-omics analysis revealed that amlexanox enhances hepatic bile acid synthesis and promotes fecal bile acid excretion. Notably, amlexanox reprogrammed gut microbiota, robustly increasing the abundance of Akkermansia muciniphila, a probiotic known to improve metabolic dysfunction. These findings uncover the multifaceted therapeutic potential of amlexanox in treating MASH and atherosclerosis by targeting bile acid metabolism, gut microbiota, hepatic inflammation, and fibrosis. Our study highlights amlexanox as a promising candidate for clinical applications.

解锁amlexanox在MASH的治疗潜力与洞察胆汁酸代谢和微生物组。
代谢功能障碍相关脂肪性肝炎(MASH)已成为与肥胖和糖尿病相关的全球性健康问题。它正在成为肝硬化和肝细胞癌(HCC)等终末期肝病的主要病因。尽管其日益流行,有效的药物治疗仍然有限,强调迫切需要新的干预措施。Amlexanox是一种非典型i - κ b激酶抑制剂,在肥胖小鼠和人类患者中已被证明具有恢复胰岛素敏感性和葡萄糖稳态的潜力。在这里,我们旨在评估氨lexanox在血脂异常相关疾病(特别是MASH和HCC)中的治疗潜力,并阐明其潜在机制。我们使用GAN饮食喂养的Ldlr -/-小鼠,这些小鼠同时发生肥胖、MASH和动脉粥样硬化,以概括人类代谢综合征和相关并发症。发病后口服氨lexanox观察其治疗效果。我们的研究表明,即使是低剂量的氨lexanox也能显著逆转MASH,几乎完全阻止了MASH向HCC的进展。表型和转录组学研究均显示,氨lexanox可显著改善mash相关的血脂异常、肝脂肪变性、炎症、肝损伤和肝纤维化。此外,多组学分析显示,氨lexanox促进肝脏胆汁酸合成并促进粪便胆汁酸排泄。值得注意的是,氨lexanox对肠道微生物群进行了重新编程,显著增加了嗜粘菌Akkermansia muciniphila的丰度,这是一种已知可以改善代谢功能障碍的益生菌。这些发现揭示了氨lexanox通过靶向胆汁酸代谢、肠道微生物群、肝脏炎症和纤维化治疗MASH和动脉粥样硬化的多方面治疗潜力。我们的研究强调了氨lexanox作为临床应用的有前途的候选人。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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