ZLN005 is a potent and cell-specific transcriptional activator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)[1]. PGC-1α is a key transcriptional coactivator primarily regulating mitochondrial biogenesis and oxidative phosphorylation processes[2]. ZLN005 is commonly used in research related to diseases such as diabetes, mitochondrial aging, and sepsis[3,4].
In vitro, pretreatment of THP-1 cells with ZLN005 (1μM) for 48h, followed by stimulation with 1μg/mL lipopolysaccharide (LPS), significantly increased PGC-1α mRNA expression and restored the mitochondrial DNA copy number reduced by LPS stimulation[5]. Treatment of differentiated human retinal pigment epithelial ARPE-19 cells with ZLN005 (10μM) for 24h significantly reduced mitochondrial superoxide production[6].
In vivo, ZLN005 (12mg/kg/day; 3 days) administered via intraperitoneal injection to C57BL/6 mice with cecal ligation and puncture (CLP)-induced sepsis significantly improved the 6-day survival rate (from 0% to 30%)[5]. In a perioperative neurocognitive disorder (PND) mouse model, daily intraperitoneal injection of ZLN005 (7.5mg/kg/day) from 3 days before surgery until 1 day after surgery significantly reduced levels of the pro-inflammatory cytokines IL-6 and IL-1β in the hippocampus and cerebral cortex at 24h post-surgery, alleviating neuroinflammation[7]. Pretreatment of C57BL/6 mice with ZLN005 (12mg/kg/day) via intraperitoneal injection for 3 days prior to hepatic ischemia-reperfusion injury (IRI) surgery significantly decreased serum levels of ALT, AST, and LDH and reduced the area of liver tissue necrosis[8].
References:
[1] ZHANG W, XIONG H, PANG J, et al. PGC-1α overexpression promotes mitochondrial biogenesis to protect auditory cells against cisplatin-induced cytotoxicity[J]. Journal of Bio-X Research, 2019, 2(2): 81-86.
[2] LIU Y, BAI H, GUO F, et al. PGC-1α activator ZLN005 promotes maturation of cardiomyocytes derived from human embryonic stem cells[J]. Aging (Albany NY), 2020, 12(8): 7411.
[3] ZHAI M, HU H, ZHENG Y, et al. PGC1α: An emerging therapeutic target for chemotherapy-induced peripheral neuropathy[J]. Therapeutic Advances in Neurological Disorders, 2023, 16: 17562864231163361.
[4] QIAN L, ZHU Y, DENG C, et al. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases[J]. Signal Transduction and Targeted Therapy, 2024, 9(1): 50.
[5] SUZUKI Y, KAMI D, TAYA T, et al. ZLN005 improves the survival of polymicrobial sepsis by increasing the bacterial killing via inducing lysosomal acidification and biogenesis in phagocytes[J]. Frontiers in Immunology, 2023, 14: 1089905.
[6] SATISH S, PHILIPOSE H, ROSALES M A B, et al. Pharmaceutical induction of PGC-1α promotes retinal pigment epithelial cell metabolism and protects against oxidative damage[J]. Oxidative Medicine and Cellular Longevity, 2018, 2018(1): 9248640.
[7] WU X, DING S, WANG G, et al. ZLN005 reduces neuroinflammation and improves mitochondrial function in mice with perioperative neurocognitive disorders[J]. Journal of Inflammation Research, 2024, 17: 8135-8146.
[8] TOHME C, HAYKAL T, YANG R, et al. ZLN005, a PGC-1α Activator, Protects the Liver against Ischemia–Reperfusion Injury and the Progression of Hepatic Metastases[J]. Cells, 2024, 13(17): 1448.
ZLN005是一种强效且具有细胞特异性的过氧化物酶体增殖激活受体-γ辅激活因子-1α（PGC-1α）转录激活剂[1]。PGC-1α是关键的转录共激活因子，主要调控线粒体生物合成和氧化磷酸化过程[2]。ZLN005通常用于糖尿病、线粒体衰老和脓毒症等相关疾病的研究[3,4]。
在体外，ZLN005（1μM）预处理THP-1细胞48h，随后加入1μg/mL脂多糖（LPS）刺激，显著提高了PGC-1α的mRNA表达，并恢复了因LPS刺激而下降的线粒体DNA拷贝数[5]。ZLN005（10μM）处理分化的人视网膜色素上皮ARPE-19细胞24h，显著减少了线粒体超氧化物的生成[6]。
在体内，ZLN005（12mg/kg/day; 3 days）通过腹腔注射治疗由盲肠结扎穿刺（CLP）诱导的脓毒症C57BL/6小鼠，显著提高了小鼠6天内的生存率（从0%提升至30%）[5]。从手术前3天至手术后1天，每日一次腹腔注射ZLN005（7.5mg/kg/day）治疗围术期神经认知障碍（PND）模型小鼠，显著降低了手术后24h海马体和大脑皮质中促炎细胞因子IL-6和IL-1β的水平，改善了神经炎症[7]。ZLN005（12mg/kg/day）通过腹腔注射预处理C57BL/6小鼠3天，后进行肝脏缺血再灌注（IRI）手术，显著降低了血清中ALT、AST和LDH的水平，减少了肝组织坏死面积[8]。