Deiodinases' Inhibitors: A Double-Edged Sword

The deiodinase enzymes are the gatekeepers of the peripheral Thyroid Hormone (TH) metabolism since they catalyze the activation of the prohormone Thyroxine (T4) into the active Triiodothyronine (T3), as well as their inactivation into metabolically inactive forms. Type I and Type II Deiodinases, Type I Deiodinase (D1) and D2, respectively, catalyze the T4-to-T3 conversion, while Type III Deiodinase, D3, terminates the THs action converting T4 into reverse T3 (rT3) and T3 into T2. Deiodinases are sensitive rate-limiting components within the hormonal axis and their enzymatic dysregulation is a common occurrence in several pathological conditions, including cancer. As a result, these enzymes are a potential source of interest for the development of pharmacological compounds exhibiting modulatory effects. The current arsenal of inhibitors for these enzymes is still limited. To date, a significant challenge in the development of deiodinases' inhibitors is the achievement of enzyme selectivity and tissue specificity without disrupting TH regulation in the surrounding healthy tissues. Furthermore, deiodinases were shown to be potent regulators of the neoplastic processes, and their expression is altered in tumors, predisposing to increased aggressiveness and progression toward metastasis. However, especially in the cancer context, this design is complicated by the spatial and temporal heterogeneity of deiodinases expression, expressed as inter-tumoral variability across different cancer types, intra-tumoral variability among distinct tumor regions or cell populations within the same tumor type, and dynamic changes over time. Nevertheless, deiodinases' inhibitors hold promise as a novel class of cancer therapeutics. Here, we proposed an overview of the actual knowledge of deiodinases' inhibitors, highlighting their potentials and limitations. Future research should focus on identifying the most effective inhibitors, refining delivery mechanisms, and optimizing treatment regimens to minimize side effects while maximizing therapeutic efficacy.