HEX-1 reduces colitis-driven colorectal cancer via inactivating the prolyl isomerase PIN1 sensitization and remodeling the gut microbiota

Metabolic reprogramming, a pivotal hallmark of cancer, plays a crucial role in both the initiation and progression of colorectal cancer (CRC). Despite the vast unknowns surrounding the identity and biological activities of most natural metabolites in diseases, our study, utilizing native metabolomics results through GC-MS/MS, identified a small molecule, 4,4-Dimethyl-2-cyclohexen-1-one, named HEX-1 in the serum of CRC patients. We have further explored and assessed its biological activities. HEX-1 suppressed the proliferation of cancer cells and tumorigenesis via the inactivation and sensitization of PIN1. Notably, HEX-1 exhibits similar functional effects as all-trans retinoic acid (atRA) but stands out by not inducing the degradation of PIN1 mRNA or protein expression, unlike biological compounds associated with atRA. HEX-1 demonstrated the ability to induce G1/S arrest in vitro and ameliorate the progression of inflammatory CRC in mice by remodeling the gut microbiota. As volatile organic compounds (VOCs), HEX-1 could be detected feasibly. Its unique ability to penetrate whole cell populations positions it as a promising approach for cancer therapy and as an enhancer for chemotherapy and immunotherapy. The findings suggest that HEX-1 holds the potential as a valuable addition to the armamentarium against CRC.