抗肾间质纤维化新药——氟非尼酮通过调控硫化氢含量影响线粒体生物合成的机制研究

Renal interstitial fibrosis is a serious threaten to human health. Fluorofenidone is a novel anti-fibrotic drug independently developed by our research group, but its target remains unknown. Recently, we used differential proteomics experiments to search for the targets of Fluorofenidone and found that the expression of cystathion-beta-synthase (CBS) was significantly reduced during renal interstitial fibrosis. CBS is a rate-limiting enzyme for the production hydrogen sulfide (H2S) in the body. Studies have reported that hydrogen sulfide can affect mitochondrial biosynthesis by regulating PGC family proteins, and mitochondrial biosynthesis is of great significance for maintaining normal mitochondrial structure and function. The preliminary experimental results of this project showed that Fluorofenidone could increase the expression of CBS in renal tissue, increase the content of H2S, and reduce mitochondrial damage. In this project, gene expression intervention, electron microscope, flow cytometry and other research methods will be comprehensively used in in vivo and in vitro experiments to further clarify that Fluorofenidone can promote mitochondrial biosynthesis, reduce mitochondrial damage and inhibit renal interstitial fibrosis by improving the expression of hydrogen sulfide. This study will not only explore the pharmacological mechanism of Fluorofenidone against renal interstitial fibrosis, but also reveal a new mechanism of the influence of hydrogen sulfide on mitochondrial biosynthesis during renal interstitial fibrosis.

肾间质纤维化严重危害人类健康，其发病机制复杂，治疗困难。氟非尼酮是本课题组自主研发的新型抗纤维化药物，但其作用靶点仍未查明。近期我们利用差异蛋白质组学实验寻找氟非尼酮作用靶点，发现：肾间质纤维化过程中，胱硫醚-β-合成酶（CBS）表达显著减少。CBS是体内硫化氢（H2S）产生的限速酶。研究报道，硫化氢能通过调节PGC家族蛋白影响线粒体生物合成，而线粒体生物合成对维持正常线粒体结构和功能具有重要意义。本课题预实验结果表明：氟非尼酮能提高肾组织中CBS表达，提高H2S含量，减轻线粒体损伤。本课题将在体内外实验中，综合运用基因表达干预、电子显微镜、流式细胞术等研究手段，进一步阐明氟非尼酮通过提高硫化氢含量，促进线粒体生物合成，减轻线粒体损伤，抑制肾间质纤维化。本课题的开展不仅能发掘氟非尼酮抗肾间质纤维化的药理学机制，而且能揭示肾间质纤维化过程中硫化氢影响线粒体生物合成的新机制。

肾间质纤维化严重危害人类健康，其发病机制复杂，治疗困难。氟非尼酮是本课题组自主研发的新型抗纤维化药物，但其具体作用靶点仍未查明。近期我们利用差异蛋白质组学实验寻找氟非尼酮作用靶点，发现：肾间质纤维化过程中，胱硫醚-β-合成酶（CBS）表达显著减少。CBS是体内硫化氢（H2S）产生的限速酶。本课题预实验结果表明：氟非尼酮能提高肾组织中CBS表达，提高H2S含量。在本研究中，我们通过细胞及动物实验发现，氟非尼酮可以通过调节硫化氢含量，减轻线粒体损伤，促进线粒体生物合成，改善线粒体功能，从而发挥抗肾间质纤维化作用。本研究的开展不仅为氟非尼酮治疗肾纤维化提供了新的理论基础，有助于指导临床用药，还为开发新的抗纤维化药物提供了理论依据。