Unravelling the role of melanogenesis in melanoma: oncogenic crosstalk and therapeutic prospects

Skin is the largest and outermost organ of the human body, composed of diverse tissues and cell types that work in concert to maintain physiological homeostasis. Skin pigment, melanin is synthesized by a physiological process termed as melanogenesis in a highly specialized cell type termed as melanocytes, located in the basal layer of the epidermis. Among the various types of skin cancers melanoma is the most aggressive form of skin cancer, originating from melanocytes due to mutations in cancer-critical genes, leading to uncontrolled proliferation, progression, and metastasis. Although melanoma accounts for about 1% of all skin cancers, but it is the most lethal, accounting for roughly 80% of all skin cancer-related deaths. The global incidence of melanoma is steadily rising, influenced by a combination of environmental and genetic factors. Among environmental contributors, ultraviolet (UV) radiation—particularly UV-B and UV-A—is a significant risk factor, while inherited genetic mutations also play a critical role in melanoma susceptibility and progression. Although several effective systemic therapies for melanoma have been established and resistance mechanisms have been extensively studied, a complete understanding of the molecular processes driving melanoma progression and therapy resistance continues to evolve. In melanoma, hyper-activation of signalling transduction pathways like Mitogen activating protein kinases (MAPK) due to BRAF mutation and Phosphoinositol-3 kinase (PI3K) due to PTEN mutation leads further dysregulation of melanogenesis regulating pathways leading to abnormal synthesis of melanin pigment, which in turn leads the progression of melanoma. The role of melanogenesis and its dysregulation in melanoma has not been fully explored and limited number of studies have been done so far. In this study, we aim to comprehensively summarize current insights of melanogenesis in melanoma pathophysiology, with a particular emphasis on the interplay between oncogenic drivers and melanogenesis-associated signaling pathways. We further provide perspectives, how it might be as explored as therapeutic target in melanoma with/without existing treatment options.