Tian Xinyuan, Bai Xiaoping, Han Yunqi, Ye Yu, Peng Meiling, Cui Hongwei, Li Kai
School of Pharmacy, Inner Mongolia Medical University, Hohhot, 010107, Inner Mongolia Autonomous Region, China.
Department of Radiation Oncology, Baotou Cancer Hospital, Baotou, 014030, Inner Mongolia Autonomous Region, China.
Mol Genet Genomics. 2025 Apr 8;300(1):41. doi: 10.1007/s00438-025-02243-9.
PPAR γ, as a widely present receptor in tissues, plays a key role in lipid metabolism, energy balance, inflammatory response, and cell differentiation. It plays an important role in the occurrence and development of various tumors, including prostate cancer, gastric cancer, lung cancer, etc., by regulating lipid metabolism. However, the specific mechanism by which it affects lung cancer growth is not yet clear. To investigate how PPAR γ affects lung cancer cell growth by altering ALDH1A3 levels through its impact on lipid metabolism. Bioinformatics analysis was used to predict the correlation between PPAR γ, ALDH1A3 and lung cancer. Based on the results of bioinformatics analysis, PPAR γ activator (Pioglitazone, Pio) and ALDH1A3 inhibitor (diethylaminobenzaldehyde, DEAB) were used to act on lung cancer cells and observe their growth. After measuring the IC50 value of the drug in vitro experiments, lipid metabolomics analysis was conducted to identify the significant changes in differential metabolites and metabolic pathways under the combined influence of Pio and DEAB. Through bioinformatics analysis, it was found that there were significant differences in the levels of PPAR γ and ALDH1A3 between lung cancer and normal lung tissues, and ALDH1A3 was positively correlated with PPAR γ. AUC analysis found that PPAR γ and ALDH1A3 have good predictive value in the diagnosis and prognosis of lung cancer. GSEA enrichment analysis showed that PPAR γ and ALDH1A3 were significantly correlated with lipid oxidation. Combining relevant literature to demonstrate the inhibitory effect of PPAR γ receptors on lung cancer cells and the ability of PPAR γ activation to inhibit ALDH1A3 levels. Further in vitro CCK-8 and IC50 measurements of lung cancer cells A549 and H1299 were conducted, followed by non targeted lipidomics analysis. It was found that the metabolic pathways upregulated by activation of PPAR γ and inhibition of ALDH1A3 included glycerophospholipid metabolism, cholesterol metabolism, arachidonic acid metabolism, and fat digestion and absorption, with glycerophospholipid metabolism pathway accounting for the highest percentage. Conclusion: PPAR γ activation can inhibit the production of ALDH1A3, alter the glycerophospholipid metabolism pathway, and thus inhibit the proliferation of lung cancer cells. This study confirms that PPAR γ affects lung cancer proliferation by influencing the glycerophospholipid metabolism pathway.
PPARγ作为一种在组织中广泛存在的受体，在脂质代谢、能量平衡、炎症反应和细胞分化中起关键作用。它通过调节脂质代谢，在包括前列腺癌、胃癌、肺癌等多种肿瘤的发生和发展中发挥重要作用。然而，其影响肺癌生长的具体机制尚不清楚。为了研究PPARγ如何通过影响脂质代谢改变ALDH1A3水平来影响肺癌细胞生长。采用生物信息学分析预测PPARγ、ALDH1A3与肺癌之间的相关性。基于生物信息学分析结果，使用PPARγ激动剂（吡格列酮，Pio）和ALDH1A3抑制剂（二乙氨基苯甲醛，DEAB）作用于肺癌细胞并观察其生长情况。在体外实验中测定药物的IC50值后，进行脂质代谢组学分析，以确定在Pio和DEAB联合作用下差异代谢物和代谢途径的显著变化。通过生物信息学分析发现，肺癌组织与正常肺组织中PPARγ和ALDH1A3水平存在显著差异，且ALDH1A3与PPARγ呈正相关。AUC分析发现，PPARγ和ALDH1A3在肺癌的诊断和预后方面具有良好的预测价值。GSEA富集分析表明，PPARγ和ALDH1A3与脂质氧化显著相关。结合相关文献证明PPARγ受体对肺癌细胞的抑制作用以及PPARγ激活抑制ALDH1A3水平的能力。进一步对肺癌细胞A549和H1299进行体外CCK-8和IC50测定，随后进行非靶向脂质组学分析。发现激活PPARγ和抑制ALDH1A3上调的代谢途径包括甘油磷脂代谢、胆固醇代谢、花生四烯酸代谢以及脂肪消化与吸收，其中甘油磷脂代谢途径占比最高。结论：PPARγ激活可抑制ALDH1A3的产生，改变甘油磷脂代谢途径，从而抑制肺癌细胞的增殖。本研究证实PPARγ通过影响甘油磷脂代谢途径影响肺癌增殖。
