Redox report : communications in free radical research · 2026
Sirtuin 5-mediated desuccinylation of PRDX6 inhibits ferroptosis and alleviates sepsis-associated acute kidney injury.
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Lin Wenlong, Dong Caitao, Jiang Qinhong, Lou Yuanquan, Wang Long, He Ziqi
Аннотация
OBJECTIVES: To investigate the role of the SIRT5-PRDX6 axis during the pathogenesis of sepsis-associated acute kidney injury (SA-AKI).
METHODS: In vivo and in vitro sepsis models were established to evaluate oxidative stress and inflammatory responses. High-throughput proteomics analysis identified ferroptosis as a key mechanism underlying SA-AKI. The levels of HMOX1, NQO-1, GPX4, ACSL4, Fe²⁺, IL-1β, TNF-α, MDA, and GSH were measured. SIRT5 knockdown/overexpression experiments were performed in HK-2 cells, and SIRT5-deficient mice were used to explore its regulatory role. Co-immunoprecipitation (Co-IP) and site-directed mutagenesis verified SIRT5-PRDX6 interaction and desuccinylation sites.
RESULTS: Ferroptosis was critical in SA-AKI progression. In LPS-induced HK-2 cells, HMOX1, NQO-1, ACSL4, Fe²⁺, IL-1β, TNF-α, and MDA were significantly increased, whereas GSH and GPX4 were downregulated. Treatment with ferrostatin-1 (Fer-1) attenuated ferroptosis and oxidative damage. SIRT5 decreased in a time-dependent manner following LPS stimulation. SIRT5 knockdown exacerbated LPS-induced ferroptosis, whereas SIRT5 overexpression suppressed it. SIRT5 activation alleviated AKI in mice, whereas SIRT5 deficiency aggravated it. Mechanistically, SIRT5 desuccinylated PRDX6 at lysine 209, thereby inhibiting inflammatory and oxidative stress responses, attenuating ferroptosis, and ultimately ameliorating renal injury.
CONCLUSION: The SIRT5-PRDX6 axis regulates SA-AKI pathogenesis by modulating ferroptosis and represents a novel potential therapeutic target.
METHODS: In vivo and in vitro sepsis models were established to evaluate oxidative stress and inflammatory responses. High-throughput proteomics analysis identified ferroptosis as a key mechanism underlying SA-AKI. The levels of HMOX1, NQO-1, GPX4, ACSL4, Fe²⁺, IL-1β, TNF-α, MDA, and GSH were measured. SIRT5 knockdown/overexpression experiments were performed in HK-2 cells, and SIRT5-deficient mice were used to explore its regulatory role. Co-immunoprecipitation (Co-IP) and site-directed mutagenesis verified SIRT5-PRDX6 interaction and desuccinylation sites.
RESULTS: Ferroptosis was critical in SA-AKI progression. In LPS-induced HK-2 cells, HMOX1, NQO-1, ACSL4, Fe²⁺, IL-1β, TNF-α, and MDA were significantly increased, whereas GSH and GPX4 were downregulated. Treatment with ferrostatin-1 (Fer-1) attenuated ferroptosis and oxidative damage. SIRT5 decreased in a time-dependent manner following LPS stimulation. SIRT5 knockdown exacerbated LPS-induced ferroptosis, whereas SIRT5 overexpression suppressed it. SIRT5 activation alleviated AKI in mice, whereas SIRT5 deficiency aggravated it. Mechanistically, SIRT5 desuccinylated PRDX6 at lysine 209, thereby inhibiting inflammatory and oxidative stress responses, attenuating ferroptosis, and ultimately ameliorating renal injury.
CONCLUSION: The SIRT5-PRDX6 axis regulates SA-AKI pathogenesis by modulating ferroptosis and represents a novel potential therapeutic target.