异常糖酵解与线粒体代谢是多发性骨髓瘤（MM）重要代谢特点，与疗效预后密切相关。ZLN005是一种代谢调节药物，调控正常组织代谢，但对肿瘤代谢有何影响，目前尚无报道。本课题预实验发现ZLN005可显著抑制MM糖、乳酸及谷氨酰胺代谢，降低过氧化物酶体增殖物激活受体γ辅激活因子-1α(PGC-1α)表达，并诱导MM细胞凋亡。而本课题前期研究发现PGC-1α是调控MM异常代谢的关键因子。据此推测ZLN005通过PGC-1α调控糖酵解及线粒体代谢，导致MM凋亡。本课题拟结合临床资料及体内外实验分析ZLN005对MM异常代谢及凋亡的影响，采用CRISPR/Cas9等基因技术研究ZLN005是否通过PGC-1α对线粒体代谢及糖酵解发挥调控，证实ZLN005通过PGC-1α调控多个代谢通路关键因子影响代谢并导致MM凋亡，探讨ZLN005干预代谢实现改善MM疗效、预后的可行性及潜在机制，为MM治疗提供新策略

Aberrant aerobic glycolysis and mitochondrial metabolism are important features of multiple myeloma(MM) metabolism, and closely correlated with efficacy and prognosis of MM. As a regulator of metabolism, ZLN005 regulates metabolism of normal tissues and cells, however, its effect on tumor metabolism has not been reported. Our preliminary study found that ZLN005 could effectively inhibit the sugar, lactic acid and glutamine metabolism of MM, reduce expression of peroxisome proliferator-activated receptor γ coactivator-1 α(PGC-1α) and significantly induce apoptosis of MM cells. Meanwhile, our previous studies have revealed that PGC-1α play important roles in regulation of MM abnormal metabolisms. Accordingly, we speculate that ZLN005 regulates glycolysis and mitochondrial metabolism via targeting PGC-1α, leading to apoptosis of MM. Next, we plan to evaluate the impact of ZLN005 on abnormal metabolism and apoptosis in MM by analyzing clinical samples and performing in-vitro and in-vivo studies, to study whether ZLN005 exerts its effects on mitochondrial metabolism and glycolysis via regulation of PGC-1α by CRISPR/Cas9 gene editing technology, aiming to demonstrate that the impaired metabolism and apoptosis of MM cells caused by ZLN005 is realized by PGC-1α regulated expressions of several key factors of metabolism pathways, and the feasibility and possible mechanism of ZLN005 targeting metabolism to improve efficacy and prognosis of MM will finally be evaluated. Our work will provide a new treatment strategy for treating MM.