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Anti-Necroptotic Effects of Itaconate and its Derivatives

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Abstract

Itaconate is an unsaturated dicarboxylic acid that is derived from the decarboxylation of the Krebs cycle intermediate cis-aconitate and has been shown to exhibit anti-inflammatory and anti-bacterial/viral properties. But the mechanisms underlying itaconate’s anti-inflammatory activities are not fully understood. Necroptosis, a lytic form of regulated cell death (RCD), is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) signaling. It has been involved in the pathogenesis of organ injury in many inflammatory diseases. In this study, we aimed to explore whether itaconate and its derivatives can inhibit necroptosis in murine macrophages, a mouse MPC-5 cell line and a human HT-29 cell line in response to different necroptotic activators. Our results showed that itaconate and its derivatives dose-dependently inhibited necroptosis, among which dimethyl itaconate (DMI) was the most effective one. Mechanistically, itaconate and its derivatives inhibited necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling and the oligomerization of MLKL. Furthermore, DMI promoted the nuclear translocation of Nrf2 that is a critical regulator of intracellular redox homeostasis, and reduced the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide (mtROS) that were induced by necroptotic activators. Consistently, DMI prevented the loss of mitochondrial membrane potential induced by the necroptotic activators. In addition, DMI mitigated caerulein-induced acute pancreatitis in mice accompanied by reduced activation of the necroptotic signaling in vivo. Collectively, our study demonstrates that itaconate and its derivatives can inhibit necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling, highlighting their potential applications for treating necroptosis-associated diseases.

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Funding

This work was supported by Guangzhou Basic and Applied Basic Foundation (202201010725), the Fundamental Research Funds for the Central Universities (No. 21622318), and the National Natural Science Foundation of China (Nos. 81873064 and 81773965).

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  1. Si-tao Ni, Qing Li, and Ying Chen are authors equally contributed to this work.

Authors and Affiliations

  1. Department of Immunobiology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Si-tao Ni, Qing Li, Ying Chen, Fu-li Shi, Li-sha Yuan, Rong Xu, Ying-qing Gan, Na Lu, Ya-ping Li, Zhi-ya Zhou, Xian-hui He & Dong-yun Ouyang

  2. Department of Nephrology, the First Affiliated Hospital of Jinan University, Guangzhou, 510630, China

    Tak-sui Wong & Bo Hu

  3. Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China

    Li-hui Xu

  4. Department of Clinical Laboratory, the Fifth Affiliated Hospital of Jinan University, Heyuan, 517000, China

    Xian-hui He

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Contributions

Ni S, Li Q, Chen Y, Yuan L, Lu N, and Zhou Z carry out the in vitro research. Shi F, Wong T, Xu R, Gan Y, Li Y, and Xu L performed the animal model experiments. Ouyang D and Hu B conceived and supervised the project. Ouyang D, and He X designed this study. Ni S, Hu B, Ouyang D, and He X analyzed the data. Ni S, Ouyang D, and He X prepared and edited the manuscript. All authors contributed to the article and approved the submitted version. We also thank Prof. Yong-tang Zheng for his kindly help in this study.

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Correspondence to Xian-hui He, Bo Hu or Dong-yun Ouyang.

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Ni, St., Li, Q., Chen, Y. et al. Anti-Necroptotic Effects of Itaconate and its Derivatives. Inflammation 47, 285–306 (2024). https://doi.org/10.1007/s10753-023-01909-z

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