SLC6A6 deficiency inhibits angiogenesis by impairing mitochondrial respiration and inducing ferroptosis.

Targeting endothelial angiogenesis holds significant promise in the treatment of hypoxic/ischemic diseases and tumors. Previous studies showed that solute carrier family 6 member 6 (SLC6A6) plays critical roles in promoting cancer cell survival and proliferation. However, the role of SLC6A6 in regulating endothelial angiogenesis remains unexplored. Using gain- and loss-of-function strategies, we demonstrated that SLC6A6 deficiency inhibited angiogenesis, whereas overexpression of SLC6A6 promoted it. By analyzing data derived from The Cancer Genome Atlas (TCGA) database, we identified that high expression of SLC6A6 correlates with poor prognosis in cancer patients. Moreover, endothelial cell-specific deficiency of SLC6A6 inhibited tumor angiogenesis and growth while also impairing blood perfusion recovery after hindlimb ischemia in mice. Mechanistically, SLC6A6 deficiency disrupted mitochondrial respiratory complexes (subunits I, IV, and V), impairing endothelial cell oxidative phosphorylation, causing mitochondrial oxidative stress, driving lipid peroxidation and ferroptosis, and thus inhibiting angiogenesis. These results indicate that SLC6A6 plays a crucial role in maintaining endothelial pro-angiogenic function and mitochondrial respiratory homeostasis, highlighting SLC6A6 as a potential therapeutic target for the treatment of hypoxic/ischemic diseases and anti-angiogenic tumor therapy.