Exploring Inhibitory Impacts of Anamorelin on Colorectal Cancer Proliferation via Regulation of Transketolase

Colorectal cancer (CRC) is a major cause of cancer- related deaths worldwide and poses a significant global health challenge. Metabolic reprogramming, including transketolase (TKT) upregulation in the pentose phosphate pathway, is a hallmark of CRC. Drugs targeting TKT have shown promise in cancer treatments; however, their mechanisms are poorly understood.

In this study, by integrating bioinformatics analysis of 494 cases from the TCGA database, we identified that transketolase (TKT) may be a potential key target for colorectal cancer. Furthermore, we systematically screened the Natural Product Library for HTS (L6000) TargetMol using molecular docking technology.

Anamorelin was identified, which exhibited optimal spatial matching with the ligand in the target protein crystal structure. As a selective growth hormone secretagogue receptor (GHS-R) agonist, anamorelin has been clinically demonstrated to significantly improve appetite and increase lean body mass in patients with CRC by activating the GHS-R signaling pathway and is currently used for treating cancer cachexia in patients with advanced CRC. However, existing research has primarily focused on its metabolic benefits, and its direct effects on tumor cell proliferation, migration, and related molecular mechanisms remain unclear. This study elucidated the regulatory relationship between anamorelin and TKT in CRC, thereby addressing a critical knowledge gap in this field (Fig. 1).

These findings reveal a previously unrecognized antitumor mechanism of anamorelin through TKT inhibition. These findings provide preliminary evidence of a TKT-associated mechanism of anamorelin in CRC, offering dual benefits in cachexia management and tumor suppression, and warrant further validation in advanced preclinical models. Further preclinical and clinical validation is warranted to translate these insights into practice.

By integrating bioinformatics analysis with in vitro cellular experiments, we systematically validated the molecular mechanism whereby anamorelin inhibited tumor cell proliferation and migration via the targeted suppression of TKT. These findings provide a theoretical foundation for the development of novel metabolism-based therapeutic strategies for CRC, ultimately contributing to improved clinical outcomes.