The role of osteoprotegerin in colorectal cancer: Molecular interactions, mechanistic insights, and therapeutic implications

BACKGROUND: Despite advances in emerging therapies, colorectal cancer (CRC) incidence continues to rise and clinical outcomes remain suboptimal, highlighting the need for improved management strategies. One potential therapeutic target is osteoprotegerin (OPG), a glycoprotein which exhibits context-dependent functions by interacting with both Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) to produce anti-resorption effects and TNF-related apoptosis inducing ligand (TRAIL) to promote cell survival, potentially modulating key hallmarks of CRC progression. However, its translational potential remains underexplored. AIMS AND SCOPE: This review summarizes OPG's structure, expression, and physiological roles, followed by a comprehensive analysis of its mechanistic contributions to CRC progression. We then examine therapeutic strategies targeting OPG and its potential as a diagnostic biomarker, before concluding with perspectives on future research. KEY FINDINGS: Present evidence suggests that circulating OPG levels are associated with prognostic factors in CRC such as overall survival and metastasis rates. However, unresolved mechanistic questions remain, particularly regarding dominant cellular sources of OPG and whether circulating OPG levels directly reflect inflammatory and/or tumor dysfunction. Clinically, OPG holds promise as a biomarker for CRC, though it may be more effectively utilized within multi-marker panels rather than as a standalone biomarker. Current research has predominantly focused on the RANKL signaling pathway, leading to development of anti-RANKL therapeutics such as Denosumab, while OPG-specific therapeutics remain underdeveloped. Collectively, future research could investigate whether compartment-specific OPG levels could serve as a biomarker for CRC and predict responses to immunotherapeutics, alongside drug repurposing of existing anti-RANKL therapeutics, and non-pharmacological strategies targeting OPG.