2. Academic Validation
  3. Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression

Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression

  • Cancer Res. 2025 May 14. doi: 10.1158/0008-5472.CAN-24-3525.
Kun Wang 1,  Jingzhuo Li 2,  Hai Zhang 3,  Hongyan Ma 4,  Hong-Yong Cui 3,  Huai-Qiang Ju 5,  Jing Zhang 1,  Qing-Zhi Ma 1,  Ming Zhao 1,  Qing-Mei Zeng 1,  Jie Zou 1,  Xiu-Xuan Sun 1,  Gang Nan 1,  Meirui Qian 6,  Lin Jing 1,  Yiming Li 1,  Cai-Feng Xiong 1,  Qiu-Zi Yang 1,  Hao Wang 7,  Jian-Li Jiang 1,  Zhi-Nan Chen 8,  Liang Chen 4,  Wan Huang 1
Affiliations

Affiliations

  • 1 Air Force Medical University, Xi'an, China.
  • 2 Fourth Military Medical University, Xi'an, China.
  • 3 Air Force Medical University, Xi'an, Shaanxi province, China.
  • 4 Shanghai University, Xi'an, China.
  • 5 Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 6 Air Force Medical University, China.
  • 7 Fourth Military Medical University, China.
  • 8 Air Force Medical University, Xi'an, Shaanxi, China.
PMID: 40366632 DOI: 10.1158/0008-5472.CAN-24-3525
Abstract

Patient behavior and physiology can directly affect Cancer metabolism. Smoking is the leading risk factor for non-small cell lung Cancer (NSCLC). Here, we identified that smoking modulates lung Cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme in glycolysis, in NSCLC samples, and GAPDH K251-Su was significantly higher in patients who smoke compared to non-smokers. Exposure of lung Cancer cells to cigarette smoke extract led to increased uptake of glutamine and enhanced GAPDH K251-Su. Glutamine uptake by Cancer cells in hypoxic and nutrient-deficient microenvironments provided succinyl-CoA donors for GAPDH succinylation at K251, which was catalyzed by Acyltransferase p300. K251-Su increased GAPDH stability by suppressing TRIM4-mediated K254 ubiquitination. GAPDH K251-Su enhanced glycolysis and glutamine reductive carboxylation to meet the demands for cell growth and to support survival in hypoxic and nutrient-depleted conditions, promoting tumor growth and metastasis. These findings indicate that tobacco smoking mediates metabolic reprogramming of Cancer cells through succinylation of GAPDH to drive NSCLC progression.

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