SIRT5 Loss Drives Ferroptotic Kidney Damage in Sepsis, Mouse and Cell Study Finds

Loss of the mitochondrial enzyme SIRT5 worsens sepsis-associated acute kidney injury by tipping renal tubular cells into ferroptosis, an iron-dependent form of cell death, according to a study using a cecal ligation and puncture (CLP) mouse model and lipopolysaccharide-stimulated human HK-2 proximal tubular cells.

The researchers found that SIRT5, a mitochondrial NAD+-dependent desuccinylase, is significantly downregulated in septic kidney injury. When they specifically deleted the Sirt5 gene in renal tubules of mice, CLP-induced renal dysfunction, structural damage, and tubular cell death became more severe. Conversely, delivering SIRT5 via AAV9-mediated overexpression attenuated these pathological changes in the same model.

Mechanistically, the study traced the damage to an ACSL4/FTH1 axis. SIRT5 deficiency increased ACSL4-dependent membrane lipid remodeling and reduced FTH1-mediated iron sequestration, while also suppressing the antioxidant enzyme GPX4. The result was amplified lipid peroxidation, iron overload, and mitochondrial damage in the kidney tubules.

Experiments in SIRT5-deficient HK-2 cells reinforced the role of ACSL4 as a downstream effector: knocking down ACSL4 effectively reversed lipid peroxidation, iron accumulation, and cell death in these cells. This positioned ACSL4 as a key mediator through which SIRT5 normally restrains ferroptotic susceptibility in renal tubular cells during sepsis.

Sepsis-associated acute kidney injury is a major cause of morbidity and mortality in critically ill patients, and effective targeted therapies remain lacking, in part because the pathogenesis is incompletely understood. The authors suggest that pharmacological restoration of SIRT5 activity or blockade of ACSL4-driven ferroptosis may offer novel therapeutic avenues, though these findings derive from preclinical mouse and cell models and require further validation before any clinical application.

Subject of Research: The role of SIRT5 in regulating ferroptosis during sepsis-associated acute kidney injury

Article Title: SIRT5 deficiency exacerbates sepsis acute renal injury by activating ACSL4/FTH1 axis dependent ferroptosis

Article References: Jiang, L., Yu, X., Shan, G., He, Z., Liu, Y., Lin, W., Song, L., & Xia, Z. (2026). SIRT5 deficiency exacerbates sepsis acute renal injury by activating ACSL4/FTH1 axis dependent ferroptosis. PLOS One, 21(10), e0361332. https://doi.org/10.1371/journal.pone.0361332

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0361332

Keywords: SIRT5, ferroptosis, sepsis, acute kidney injury, ACSL4, FTH1, GPX4, lipid peroxidation, renal tubular cells, preclinical study, deficiency, exacerbates