[SENP1 reduces ferroptosis of thyroid cancer cells by regulating hypoxia-inducible factor-1α]

To explore the regulatory role of SENP1 in ferroptosis of differentiated thyroid cancer cells and its molecular mechanism.

TPC-1 cells transfected with sh-NC or sh-SENP1 plasmid were inoculated in nude mice (n=6), and tumor growth was observed. In in vitro studies, TPC-1 cells were transfected with a SENP1-over expressing plasmid, si-USP11, or si-SENP1 via Lipofectamine 3000, followed by examination with CCK-8, EdU, LDH, Calcein/PI, and cytotoxicity assay kits. Mitochondrial function of the cells was evaluated using JC-1 depolymerization and mitochondrial permeability transition pore assays, and the changes in cellular protein expression levels were analyzed using Western Blotting.

SENP1 knockdown in TPC-1 cells significantly inhibited tumor growth in nude mice. In TPC-1 cells, SENP1 overexpression significantly promoted cell proliferation and metastasis, and SENP1 knockdown produced the opposite effects. Functionally, SENP1 overexpression in TPC-1 cells obviously reduced the percentage of PI-positive cells and iron content and upregulated GPX4 protein levels, while the reverse changes were observed following si-SENP1 transfection. SENP1 overexpression also enhanced JC-1 depolymerization, increased calcein-AM/cobalt chloride fluorescence and extracellular acidification rate, and decreased oxygen consumption rate, indicating reduced mitochondrial damage. Conversely, si-SENP1 transfection exacerbated mitochondrial injury in TPC-1 cells. SENP1 overexpression significantly enhanced the protein level of hypoxia-inducible factor-1α, which was obviously lowered following sh-SENP1 transfection in TPC-1 cells.

High expression of SENP1 inhibits mitochondrial damage, reduces ferroptosis, and promotes proliferation of thyroid cancer cells by activating HIF-1α, suggesting the potential of SENP1 as a novel therapeutic target for thyroid cancer.