Emerging role of the itaconate-mediated rescue of cellular metabolic stress

Abstract

Metabolic regulations play vital roles on maintaining the homeostasis of our body. Evidence have suggested that ATF3 and nuclear factor erythroid 2–related factor 2 (NRF2) are critical for maintaining cell function, metabolism, and inflammation/anti-inflammation regulations when cells are under stress, while the upstream regulators in the stressed cells remain elusive. Recent findings have shown that tricarboxylic acid cycle metabolites such as itaconate and succinate are not just mitochondrial metabolites, but rather important signaling mediators, involving in the regulations of metabolism, immune modulation. Itaconate exerts anti-inflammatory role through regulating ATF3 and NRF2 pathways under stressed conditions. In addition, itaconate inhibits succinate dehydrogenase, succinate oxidation and thus blocking succinate-mediated inflammatory processes. These findings suggest itaconate-ATF3 and itaconate-NRF2 axes are well-coordinated machineries that facilitate the rescue against cellular stress. Here, we review these fascinating discoveries, a research field may help the development of more effective therapeutic approach to manage stress-induced inflammation, tissue damage, and metabolic disorder.

The Role of Activating Transcription Factor 3 in Metformin’s Alleviation of Gastrointestinal Injury Induced by Restraint Stress in Mice

“…Notably, the efficacy of metformin in protecting the GI tract was more pronounced in wild-type mice than in mutant mice lacking ATF3, suggesting ATF3’s involvement in metformin-mediated rescue. ATF3 exerts an anti-inflammatory role by suppressing pro-inflammatory cytokines and chemokines, inhibiting NF-κB and AP-1-driven promoters, and promoting immune homeostasis [ 32 , 33 , 34 ]. It regulates gene expression to mitigate inflammation and maintain immune balance [ 32 , 33 , 34 ].…”

“…ATF3 exerts an anti-inflammatory role by suppressing pro-inflammatory cytokines and chemokines, inhibiting NF-κB and AP-1-driven promoters, and promoting immune homeostasis [ 32 , 33 , 34 ]. It regulates gene expression to mitigate inflammation and maintain immune balance [ 32 , 33 , 34 ]. ATF3 has also been implicated in the metformin-induced feedback loop between AMPK and GDF15, which contributes to the drug’s anti-diabetic effects [ 35 ].…”

“…In addition to its anti-inflammatory properties, ATF3 also plays a critical role in promoting cell survival and protecting against different stresses [ 32 , 33 , 34 ]. It modulates the expression of genes involved in cell survival pathways [ 32 , 33 , 36 ].…”

“…In addition to its anti-inflammatory properties, ATF3 also plays a critical role in promoting cell survival and protecting against different stresses [ 32 , 33 , 34 ]. It modulates the expression of genes involved in cell survival pathways [ 32 , 33 , 36 ]. ATF3 enables cells to adapt to stressful conditions and enhances their resistance to apoptosis, ensuring cell survival and preserving tissue integrity [ 33 , 36 , 37 ].…”

Activating Transcription Factor 3 Protects against Restraint Stress-Induced Gastrointestinal Injury in Mice

“…As a stress-induced transcription factor, ATF3 plays critical roles in the regulation of cell survival, metabolism, immunity, and oncogenesis [ 12 , 80 ]. Various cellular stress signals, such as endoplasmic reticulum stress, cytokines, chemokines, and bacterial lipopolysaccharide, are associated with ATF3 induction [ 12 ].…”