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.

口腔潜在恶性疾病 (OPMD) 是口腔鳞状细胞癌 (OSCC) 的先兆。细胞能量代谢失调是癌细胞的一个重要标志。过氧化物酶体增殖物激活受体-γ 共激活剂-1 α (PGC1α) 在线粒体能量代谢中发挥着至关重要的作用。然而，PGC1α 对 OPMDs 进展的分子机制尚不清楚。因此，我们全面研究了敲低PGC1α对人发育不良口腔角质形成细胞（DOKs）的影响，包括细胞增殖、细胞周期、凋亡、异种移植肿瘤、线粒体DNA（mtDNA）、线粒体电子传递链复合物（ETC）、活性氧（ ROS）、耗氧率（OCR）、细胞外酸化率（ECAR）和葡萄糖摄取。我们发现敲低PGC1α可显着抑制体外DOKs的增殖和体内肿瘤的生长，诱导S期阻滞，并抑制PI3K/Akt信号通路，而不影响细胞凋亡。从机制上讲，下调 PGC1α 会降低 mtDNA、ETC 和 OCR，同时通过调节乳酸脱氢酶 A (LDHA) 增强 ROS、葡萄糖摄取、ECAR 和糖酵解。此外，SR18292（PGC1α 的抑制剂）可诱导 DOK 氧化磷酸化功能障碍，并减缓 DOK 异种移植肿瘤的进展。因此，我们的工作表明 PGC1α 通过重新编程能量代谢和干扰能量代谢在细胞增殖中发挥至关重要的作用，作为 OPMD 的潜在治疗靶点。