Target engagement of biguanides in colorectal carcinoma

Colorectal cancer (CRC) continues to be the largest reason for disease-related illnesses and fatalities globally, emphasizing the critical necessity finding new along with affordable therapy approaches. Biguanides, particularly metformin and phenformin, have emerged as promising anticancer agents by perturbing metabolic networks that are critical for cancer cell survival. Extensive preclinical and clinical investigations indicate that biguanides exert their anticancer effects in colorectal cancer chiefly by altering mitochondrial bioenergetics and downstream signalling pathways. The primary approach includes inhibiting cellular respiration cycle complexes I, thereby lowering phosphate oxidation along with the production of ATP while increasing the AMP/ATP balance. This physiological strain stimulates AMP-activated protein kinase (AMPK), a crucial physiological detector, which suppresses mammalian target of rapamycin complex 1 (mTORC1) signalling by inhibiting protein production, growth of cells and tumour development. Biguanides affect insulin/IGF-1 signalling, oxidative balance, and cellular inflammation through HIF-1α and NF-κB, in addition to AMPK-related processes. Significantly, specific involvement throughout biguanides seems to be highly contextually regulated by tumour genetics, energy metabolism characteristics, gastrointestinal microbiota, as well as nutritional accessibility, which somewhat could clarify the variance in patient outcomes among CRC subsets. Recent investigations reveal that biguanides improve therapeutic sensitivity to conventional chemo-radiotherapy and promote ferroptosis and additional non-apoptotic death pathways, highlighting their translational potential. This review integrates molecular and signalling insights to elucidate how biguanides engage key metabolic targets in CRC, leading to coordinated metabolic reprogramming and tumour suppression. A better knowledge of specific involvement as well as prospective indicators could assist with identifying individuals along with maximize the reconfiguration of biguanides as supplementary or independent medicines in colon cancer treatment.