Biochimica et biophysica acta. Molecular basis of disease · 2026
Succinylation modification on NFS1 ameliorates the glucose starvation-induced ferroptosis through maintaining mitochondrial iron homeostasis in oral squamous cell carcinoma cells.
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Ling Hang, Qing Limin, Zuo Liang, Wang Honghan, Cai Xu, Liu Yan, Tian Hao
Аннотация
BACKGROUND: NFS1 (cysteine desulfurase), an essential enzyme in iron-sulfur (FeS) cluster biogenesis, is a key regulator of ferroptosis. In oral squamous cell carcinoma (OSCC), NFS1 is up-regulated and undergoes enhanced succinylation under glucose starvation. This study aims to elucidate the mechanistic role of NFS1, particularly through ferroptosis, in OSCC progression.
METHODS: The expression ofNFS1 and its prognostic value in OSCC were first explored using bioinformatics analysis and subsequently validated in clinical specimens. Cell viability and invasion were assessed via CCK8 and transwell assays, respectively. Aconitase 1 (ACO1) activity and live/dead cell assay were measured using commercial kits. Label-free quantitative succinylation proteomics and co-immunoprecipitation (Co-IP) were performed to analyze NFS1 succinylation and its interaction with KAT2A. Mitochondrial localization of NFS1 was visualized by immunofluorescence. Intracellular and mitochondrial Fe2+ levels, lipid peroxidation, and mitochondrial reactive oxygen species were quantified with specific fluorescent probes.
RESULTS: NFS1 gene is up-regulated in OSCC and correlates with poor patient prognosis. Elevated NFS1 expression enhances the resistance of OSCC cells to glucose starvation, promoting both viability and invasiveness. KAT2A-mediated succinylation facilitates the mitochondrial translocation of NFS1, which in turn augments mitochondrial iron uptake and suppresses ferroptosis. The KAT2A-NFS1 axis helps maintain mitochondrial iron homeostasis, thereby mitigating ferroptosis under glucose-starved conditions. In OSCC xenograft mouse models, NFS1 promotes tumor proliferation and growth by facilitating mitochondrial iron transport.
CONCLUSIONS: KAT2A-induced succinylation of NFS1 inhibits ferroptosis in glucose-deprived OSCC cells by sustaining mitochondrial iron homeostasis, ultimately driving tumor proliferation and growth. These findings underscore the therapeutic potential of targeting the NFS1-ferroptosis axis in OSCC treatment.
METHODS: The expression ofNFS1 and its prognostic value in OSCC were first explored using bioinformatics analysis and subsequently validated in clinical specimens. Cell viability and invasion were assessed via CCK8 and transwell assays, respectively. Aconitase 1 (ACO1) activity and live/dead cell assay were measured using commercial kits. Label-free quantitative succinylation proteomics and co-immunoprecipitation (Co-IP) were performed to analyze NFS1 succinylation and its interaction with KAT2A. Mitochondrial localization of NFS1 was visualized by immunofluorescence. Intracellular and mitochondrial Fe2+ levels, lipid peroxidation, and mitochondrial reactive oxygen species were quantified with specific fluorescent probes.
RESULTS: NFS1 gene is up-regulated in OSCC and correlates with poor patient prognosis. Elevated NFS1 expression enhances the resistance of OSCC cells to glucose starvation, promoting both viability and invasiveness. KAT2A-mediated succinylation facilitates the mitochondrial translocation of NFS1, which in turn augments mitochondrial iron uptake and suppresses ferroptosis. The KAT2A-NFS1 axis helps maintain mitochondrial iron homeostasis, thereby mitigating ferroptosis under glucose-starved conditions. In OSCC xenograft mouse models, NFS1 promotes tumor proliferation and growth by facilitating mitochondrial iron transport.
CONCLUSIONS: KAT2A-induced succinylation of NFS1 inhibits ferroptosis in glucose-deprived OSCC cells by sustaining mitochondrial iron homeostasis, ultimately driving tumor proliferation and growth. These findings underscore the therapeutic potential of targeting the NFS1-ferroptosis axis in OSCC treatment.