2. Academic Validation
  3. m6A methylation-mediated PGC-1α contributes to ferroptosis via regulating GSTK1 in arsenic-induced hepatic insulin resistance

m6A methylation-mediated PGC-1α contributes to ferroptosis via regulating GSTK1 in arsenic-induced hepatic insulin resistance

  • Sci Total Environ. 2023 Sep 18;905:167202. doi: 10.1016/j.scitotenv.2023.167202.
Jingyuan Zhang 1,  Jinwei Song 1,  Shuang Liu 1,  Yuhan Zhang 1,  Tianming Qiu 1,  Liping Jiang 2,  Jie Bai 3,  Xiaofeng Yao 4,  Ningning Wang 5,  Guang Yang 3,  Xiance Sun 6
Affiliations

Affiliations

  • 1 Occupational and Environmental Health Department, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China.
  • 2 Experimental Teaching Center of Public Health, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China.
  • 3 Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China.
  • 4 Occupational and Environmental Health Department, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China. Electronic address: [email protected].
  • 5 Nutrition and Food Hygiene, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China. Electronic address: [email protected].
  • 6 Occupational and Environmental Health Department, School of Public Health, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China; Global Health Research Center, Dalian Medical University, No. 9 West Section Lvshun South Road, Dalian 116044, PR China. Electronic address: [email protected].
PMID: 37730054 DOI: 10.1016/j.scitotenv.2023.167202
Abstract

Arsenic exposure has been closely linked to hepatic Insulin resistance (IR) and Ferroptosis with the mechanism elusive. Peroxisome proliferator γ-activated receptor coactivator 1-α (PGC-1α) is essential for glucose metabolism as well as for the production of Reactive Oxygen Species (ROS). However, it was unclear whether there is a regulatory connection between PGC-1α and Ferroptosis. Besides, the definitive mechanism of arsenic-induced hepatic IR progression remains to be determined. Here, we found that hepatic Insulin sensitivity impaired by sodium arsenite (NaAsO2) could be reversed by inhibiting Ferroptosis. Mechanistically, we found that PGC-1α suppression inhibited the protein expression of glutathione s-transferase kappa 1 (GSTK1) via nuclear respiratory factor 1 (NRF1), thereby increasing ROS accumulation and promoting Ferroptosis. Furthermore, we showed that NaAsO2 induced hepatic IR and Ferroptosis via methyltransferase-like 14 (METTL14) and YTH domain-containing family protein 2 (YTHDF2)-mediated N6-methyladenosine (m6A) of PGC-1α mRNA. In conclusion, NaAsO2-mediated PGC-1α suppression was m6A methylation-dependent and induced Ferroptosis via the PGC-1α/NRF1/GSTK1 pathway in hepatic IR. The data might provide insight into potential targets for diabetes prevention and treatment.

Keywords

Ferroptosis; Insulin resistance; N6-methyladenosine; Peroxisome proliferator γ-activated receptor coactivator 1-α; Sodium arsenite.

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