Recent evidence indicates that a high-fat diet (HFD) can promote tumor development, especially colorectal cancer (CRC), by influencing the microbiota. Regulatory circular RNAs (circRNAs) play an important role in modulating host–microbe interactions; however, the specific mechanisms by which circRNAs influence cancer progression by regulating these interactions remain unclear. Here, we report that consumption of a HFD modulates the microbiota by specifically upregulating the expression of the noncoding RNA hsa_circ_0126925 (herein referred to as circ_0126925) in CRC. Acting as a scaffold, circ_0126925 hinders the recruitment of the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) to branched-chain amino acid transaminase 2 (BCAT2), leading to reduced degradation of BCAT2. This reduction in targeted degradation of BCAT2 can protect tumours from limited branched-chain amino acids (BCAAs) interference by improving the metabolism of BCAAs in CRC. Taken together, these data demonstrate that circ_0126925 plays a critical role in promoting the progression of CRC by maintaining BCAA metabolism and provide insight into the functions and crosstalk of circ_0126925 in host–microbe interactions in CRC.
Implications: This study preliminarily confirms that circRNAs do indeed respond to microbiota/microbial metabolites, providing further evidence for the potential development of circRNAs as diagnostic tools and/or therapeutic agents to alleviate microbiome related pathology in humans.
Organisms adapt to fasting by remodeling energy metabolism across tissues. We identify geranylgeranyl pyrophosphate synthase (GGPPS) in white adipose tissue (WAT) as a fasting-responsive regulator that orchestrates lipolysis and branched-chain amino acid (BCAA) metabolism. In mice, fasting downregulates GGPPS, destabilizing the BCAA-catabolizing enzyme BCAT2 via enhanced ubiquitination. Mechanistically, GGPPS scaffolds the deubiquitinase OTUB1 and BCAT2 to stabilize BCAT2, promoting BCAA catabolism. Elevated BCAAs activate adipocyte lipolysis and enhance hepatic fatty acid oxidation. Adipose-specific deletion of Ggpps phenocopies fasting responses, including enhanced lipolysis and systemic BCAA elevation. Conversely, BCAA supplementation promotes adipose lipolysis, protects against diet-induced obesity, and facilitates hepatic oxidative adaptation. In fasting mice, BCAA supplementation enhanced weight loss efficiency and prevented aberrant hepatic lipid accumulation. These findings identify GGPPS as a potential central node linking amino acid and lipid metabolism during early fasting within a multi-organ metabolic circuit.
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