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. 2023 Jan 24;14(1):57. doi: 10.1038/s41419-023-05599-1

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 2 — Metabolic challenges such as hypoxia and nutrient deprivation increase CPT1C expression in most cancer cells, promoting metabolic adaptation and survival in response to these environmental stressors. On the one hand, low oxygen levels promote accumulation of the HIF1α transcription factor, which is translocated to the nucleus to bind the Cpt1c promoter and activate gene transcription. On the other hand, glucose depletion and glycolysis inhibition increase the AMP/ATP ratio leading to activation of AMPK, which in turn, phosphorylates and activates the CREB transcription factor. Phosphorylated CREB increases expression of the PGC-1β and ERRα transcription factors, ultimately promoting Cpt1c transcription. PPARα activates CPT1C expression by binding directly to the promoter region. p53 is activated by DNA-damaging stimuli and binds to the first intron of the Cpt1c, thereby enhancing CPT1C expression. Interestingly, 2 different miRNAs have been described that downregulate this signaling pathway, one acting on ERRα expression, and the other on CPT1C expression.