口腔潜在恶性病变（OPMDs）是口腔鳞状细胞癌（OSCC）的前体。细胞能量代谢的失调是癌细胞的重要特征。过氧化物酶体增殖物活化受体-γ共激活因子-1α（PGC1α）在线粒体能量代谢中起着至关重要的作用。然而，PGC1α在OPMDs进展中的分子机制尚不清楚。因此，我们综合性地研究了PGC1α敲低对人类畸形口腔表皮角质细胞（DOKs）的影响，包括细胞增殖、细胞周期、凋亡、异种移植瘤、线粒体DNA（mtDNA）、线粒体电子传递链复合物（ETC）、活性氧（ROS）、耗氧速率（OCR）、细胞外酸化速率（ECAR）和葡萄糖摄取。我们发现，PGC1α敲低显著抑制了DOKs的体外增殖和体内肿瘤生长，诱导了S期阻滞，并抑制了PI3K/Akt信号通路，而不影响细胞凋亡。机制上，PGC1α的下调降低了mtDNA、ETC和OCR，同时增强了ROS、葡萄糖摄取、ECAR和糖酵解，通过调节乳酸脱氢酶A（LDHA）实现。此外，SR18292（一种PGC1α抑制剂）诱导DOKs的氧化磷酸化功能失调，并降低了DOK异种移植瘤的进展。因此，我们的工作表明，PGC1α通过重编程能量代谢和干预能量代谢在细胞增殖中起着至关重要的作用，是OPMDs的潜在治疗靶点。版权所有©2023. 四川大学华西口腔医学院。

Oral potentially malignant disorders (OPMDs) are precursors of oral squamous cell carcinoma (OSCC). Deregulated cellular energy metabolism is a critical hallmark of cancer cells. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) plays vital role in mitochondrial energy metabolism. However, the molecular mechanism of PGC1α on OPMDs progression is less unclear. Therefore, we investigated the effects of knockdown PGC1α on human dysplastic oral keratinocytes (DOKs) comprehensively, including cell proliferation, cell cycle, apoptosis, xenograft tumor, mitochondrial DNA (mtDNA), mitochondrial electron transport chain complexes (ETC), reactive oxygen species (ROS), oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake. We found that knockdown PGC1α significantly inhibited the proliferation of DOKs in vitro and tumor growth in vivo, induced S-phase arrest, and suppressed PI3K/Akt signaling pathway without affecting cell apoptosis. Mechanistically, downregulated of PGC1α decreased mtDNA, ETC, and OCR, while enhancing ROS, glucose uptake, ECAR, and glycolysis by regulating lactate dehydrogenase A (LDHA). Moreover, SR18292 (an inhibitor of PGC1α) induced oxidative phosphorylation dysfunction of DOKs and declined DOK xenograft tumor progression. Thus, our work suggests that PGC1α plays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism, acting as a potential therapeutic target for OPMDs.© 2023. West China School of Stomatology Sichuan University.