Chinese Journal of Tissue Engineering Research ›› 2025, Vol. 29 ›› Issue (35): 7578-7588.doi: 10.12307/2026.526

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Exercise prevention and treatment of insulin resistance: role and molecular mechanism of Keap1/nuclear factor erythroid2-related factor 2 signaling pathway

Liu Xuan1, Ding Yuqing1, Xia Ruohan2, Wang Xianwang2, Hu Shujuan1   

  1. 1School of Education and Physical Education, 2Department of Medicine, Yangtze University, Jingzhou 423000, Hubei Province, China 
  • Received:2024-12-23 Accepted:2025-02-20 Online:2025-12-18 Published:2025-05-06
  • Contact: Hu Shujuan, PhD, Associate professor, School of Education and Physical Education, Yangtze University, Jingzhou 423000, Hubei Province, China
  • About author:Liu Xuan, Master, School of Education and Physical Education, Yangtze University, Jingzhou 423000, Hubei Province, China Ding Yuqing, Master, School of Education and Physical Education, Yangtze University, Jingzhou 423000, Hubei Province, China Liu Xuan and Ding Yuqing contributed equally to this work.
  • Supported by:
    National Natural Science Foundation of China, No. 81974115 (to XRH); Shannan Municipal Science and Technology Plan Project, No. SNSBJKJJHXM2024023 (to WXW); Hubei Natural Science Foundation (General Program), No. JCZRYB202501311 (to HSJ); Yangtze University College Students Innovation and Entrepreneurship Training Program, No. Yz2023165 (to HSJ)

Abstract: BACKGROUND: Exercise interventions play a key role in disease prevention and treatment, which can effectively activate the nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway to prevent the occurrence and development of insulin resistance. However, the potential mechanism of Nrf2-targeting exercise therapy strategies in alleviating insulin resistance remains unclear.
OBJECTIVE: Based on the relationship between Nrf2, insulin resistance and exercise, to analyze the mechanism and influence of different exercise modes on the activation of Nrf2, thereby elucidating the potential mechanism of Nrf2-targeting exercise therapy strategies in the process of alleviating insulin resistance.
METHODS: “Diabetes mellitus, insulin, insulin resistance, nuclear factor E2 related factor 2, oxidative stress, ferroptosis, autophagy, inflammatory response, exercise” were used as search terms in Chinese and English. WanFang Database, CNKI, Google Scholar and PubMed database were searched for relevant literature from inception to October 2024, and a total of 127 core related articles were obtained according to the inclusion and exclusion criteria.
RESULTS AND CONCLUSION: (1) Keap1/Nrf2 signaling pathway, as an important endogenous antioxidant stress pathway, plays an important role in insulin resistance. Activation of Keap1/Nrf2 signaling pathway can enhance the antioxidant capacity of cells, reduce oxidative stress and inflammation, improve insulin signaling, and thus protect insulin resistance. (2) A variety of exercise methods (including aerobic exercise, resistance exercise and high-intensity intermittent exercise) can effectively activate Nrf2 signal, improve the activity of antioxidant kinase and enhance the antioxidant capacity of cells, so as to alleviate oxidative stress damage to a certain extent. (3) By activating Nrf2 signaling pathway, exercise can up-regulate the activity of antioxidant enzymes such as Heme oxygenase 1, superoxide dismutase, catalase, glutathione peroxidase, glutathione, and enhance the antioxidant capacity of cells. In addition, it can also regulate the key enzymes and proteins in the ferroptosis pathway, such as glutathione peroxidase 4, membrane iron transport protein 1, and ferritin heavy chain 1, inhibit the ferroptosis pathway and promote the balance of iron metabolism. In autophagy, the expression of autophagy related genes p62 and ATG5/7 can be enhanced, and the level of microtubule-associated protein 1 light chain 3 is increased, thus regulating autophagy process. At the same time, the activity of tumor necrosis factor-α, nuclear factor-κB, interleukin-6, interleukin-1β and other pro-inflammatory cytokines is decreased, and the inflammatory response can be effectively inhibited. These combined effects can reduce oxidative stress damage, increase insulin sensitivity and improve insulin signaling, and thus have a positive effect on improving insulin resistance. (4) Given that the Keap1/Nrf2 signaling pathway plays an important role in the pathogenesis and treatment of insulin resistance, exercise therapy strategies targeting the Keap1/Nrf2 signaling pathway will help promote the development of “exercise+drug” precision medicine for insulin resistance.

Key words: Keap1/Nrf2, insulin, insulin resistance, oxidative stress, iron metabolism, autophagy, inflammatory response, exercise, engineered tissue construction

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