Multifaceted roles of superoxide dismutases (SODs) in cellular homeostasis and cancer progression: Redox regulation and therapeutic implications

Superoxide dismutases (SODs) are critical metalloenzymes that regulate cellular redox homeostasis by catalysing the dismutation of superoxide radicals into hydrogen peroxide and oxygen, thereby mitigating oxidative stress. Comprising three isoforms - SOD1 (Cu/Zn-SOD), SOD2 (Mn-SOD), and SOD3 (ecSOD) - these enzymes are localised in distinct cellular compartments, including the cytosol, mitochondria, and extracellular matrix, respectively. SODs play pivotal roles in cellular signalling, metabolism, and protection against reactive oxygen species (ROS)-mediated damage. Dysregulation of SOD expression and activity is implicated in various pathological conditions, particularly cancer, where they influence tumour initiation, progression, metastasis, and therapy resistance. Elevated SOD1 and SOD2 levels often promote oncogenic signalling and tumour survival, whereas SOD3 exhibits context-dependent roles, balancing tumour suppression and progression. Additionally, SOD mimetics, notably manganese-based compounds such as Mn-porphyrins and Mn-salens, have emerged as promising therapeutic agents that selectively modulate oxidative stress in cancer cells, thereby enhancing the efficacy of chemotherapy and radiotherapy while protecting normal tissues. This review explores the multifaceted roles of SODs in cellular homeostasis, their involvement in cancer pathogenesis, and the therapeutic potential of SOD mimetics in redox-based cancer strategies.