Proline Metabolism in Cancer: Emerging Roles in Redox Homeostasis and Therapeutic Opportunities

Cancer is a complex disease characterized by uncontrolled proliferation and progression toward metastasis. The activation and maintenance of these processes demand increased energy production. Traditional cancer therapies often target broad energy-generating mechanisms to inhibit cancer growth. However, the field of oncology is increasingly shifting toward more potent, precise, and personalized treatment strategies. This shift has fueled interest in novel cancer metabolic pathway targets. This review focuses on proline metabolism, an amino acid pathway that has been observed to be altered across various cancer subtypes. Proline has emerged as one of the most consistently deregulated non-essential amino acids in cancer biology. Proline metabolism is intimately linked to mitochondria function and energy regulation through mechanisms such as reactive oxygen species, ATP production, and interactions with the tumor microenvironment. Due to its dichotomous nature, proline metabolism functions are highly context dependent, varying across cancer subtypes. While this provides a potential novel therapeutic target, it also presents unique challenges and knowledge gaps.