<p>Epidemiological studies have indicated a strong link between metabolic disease and an elevated risk of cancer. However, it has not been directly replicated in animal models, nor has its specific underlying mechanism been clarified. From our previous research, liver-specific SIRT1 knockout (LKO) mice developed hyperglycemia within two months and developed fatty liver with whole-body insulin resistance around nine months of age. When the mice’s age extended to one year, they presented surprisingly higher lung tumor vulnerabilities in contrast to wild type as determined by macroscopic observation and histological examination. Interestingly, all lung tumors in these mice were classified as lung adenocarcinomas. Microarray analysis revealed elevated levels of MDM2, an oncoprotein, leading to the downregulation of its target genes such as p21 and GADD45. In vitro, the disruption of MDM2 leads to impaired cell cycle checkpoints and increased cell proliferation, which is accompanied by genomic instability, eventually causing full transformation in normal lung epithelia. In addition, the heat shock factor 1 (HSF1) transcription factor was found to regulate MDM2 directly and would decrease in the nucleus under high glucose conditions. Knockdown of HSF1 in the bronchial epithelial cell line (NL20) can increase MDM2 expression and cell proliferation. Human lung adenocarcinomas also displayed elevated MDM2 levels, with a correlation between MDM2 expression and lung cancer survival rates. Collectively, our findings suggest that liver-specific <i>SIRT1</i> knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through the HSF1-MDM2 pathway. Hyperglycemia may represent an underexplored cause of lung adenocarcinomas through impairment of cell cycle checkpoints, providing valuable insights for lung cancer prevention and future precision medicine.</p>