SIRT5 deficiency exacerbates sepsis acute renal injury by activating ACSL4/FTH1 axis dependent ferroptosis
- 1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
- 2Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China
Abstract
Sepsis‑associated acute kidney injury (S‑AKI) is a major cause of morbidity and mortality in critically ill patients, yet effective targeted therapies remain lacking due to an incomplete understanding of its pathogenesis. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently been implicated in AKI, but the upstream regulators of this process in sepsis remain undefined. Here, we identify SIRT5, a mitochondrial NAD ⁺ ‑dependent desuccinylase, as a critical endogenous suppressor of ferroptosis in S‑AKI. Using a cecal ligation and puncture (CLP) murine model and lipopolysaccharide (LPS)‑stimulated HK‑2 proximal tubular cells, we show that SIRT5 expression is significantly downregulated in septic kidney injury. Renal tubular‑specific ablation of Sirt5 exacerbated CLP‑induced renal dysfunction, structural damage, and tubular cell death, whereas AAV9‑mediated SIRT5 overexpression attenuated these pathological changes. Mechanistically, SIRT5 deficiency tipped the balance of the ACSL4/FTH1 axis toward ferroptosis: it increased ACSL4‑dependent membrane lipid remodeling and reduced FTH1‑mediated iron sequestration, accompanied by suppression of the antioxidant enzyme GPX4. Consequently, lipid peroxidation, iron overload, and mitochondrial damage were markedly amplified. Notably, knockdown of ACSL4 in SIRT5‑deficient HK‑2 cells effectively reversed lipid peroxidation, iron accumulation, and cell death, establishing ACSL4 as a key downstream effector of SIRT5‑mediated ferroptosis suppression. Our findings reveal a previously unrecognized SIRT5–ACSL4/FTH1 regulatory axis that governs ferroptotic susceptibility in renal tubular cells during sepsis, and suggest that pharmacological restoration of SIRT5 activity or blockade of ACSL4‑driven ferroptosis may offer novel therapeutic avenues for S‑AKI.
Related
- NEURL1-mediated K63-ubiquitination of SLC40A1 drives ferroptosis resistance in pathological scars: Therapeutic targeting via autophagy-activating microneedles.
- METTL3-mediated m⁶A modification targets the regulation of PCBP1 expression, thereby modulating GPX4 levels and intracellular Fe²⁺ homeostasis to influence ferroptosis and contribute to juvenile sepsis-associated brain injury.
- Multi-omics analysis reveals that sleep deprivation exacerbates intestinal barrier injury via the microbiota-dependent taurodeoxycholic acid/group 3 innate lymphoid/IL-22 axis
- Sodium-dependent multivitamin transporter deficiency caused by novel SLC5A6 mutations: a clinical case and personalized mice model study
- Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma
BibTeX
@article{jiang2026sirt5,
title = {{SIRT5 deficiency exacerbates sepsis acute renal injury by activating ACSL4/FTH1 axis dependent ferroptosis}},
author = {Liliang Jiang and Xi Yu and Guang Shan and Ziqi He and Yongbo Liu and Wenlong Lin and Lingling Song and Zhongyuan Xia},
journal = {PLOS One},
year = {2026},
month = oct,
doi = {10.1371/journal.pone.0361332},
url = {https://doi.org/10.1371/journal.pone.0361332},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - SIRT5 deficiency exacerbates sepsis acute renal injury by activating ACSL4/FTH1 axis dependent ferroptosis
AU - Liliang Jiang
AU - Xi Yu
AU - Guang Shan
AU - Ziqi He
AU - Yongbo Liu
AU - Wenlong Lin
AU - Lingling Song
AU - Zhongyuan Xia
PY - 2026
DA - 2026/10/27
JO - PLOS One
DO - 10.1371/journal.pone.0361332
UR - https://doi.org/10.1371/journal.pone.0361332
AB - Sepsis‑associated acute kidney injury (S‑AKI) is a major cause of morbidity and mortality in critically ill patients, yet effective targeted therapies remain lacking due to an incomplete understanding of its pathogenesis. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently been implicated in AKI, but the upstream regulators of this process in sepsis remain undefined. Here, we identify SIRT5, a mitochondrial NAD ⁺ ‑dependent desuccinylase, as a critical endogenous suppressor of ferroptosis in S‑AKI. Using a cecal ligation and puncture (CLP) murine model and lipopolysaccharide (LPS)‑stimulated HK‑2 proximal tubular cells, we show that SIRT5 expression is significantly downregulated in septic kidney injury. Renal tubular‑specific ablation of Sirt5 exacerbated CLP‑induced renal dysfunction, structural damage, and tubular cell death, whereas AAV9‑mediated SIRT5 overexpression attenuated these pathological changes. Mechanistically, SIRT5 deficiency tipped the balance of the ACSL4/FTH1 axis toward ferroptosis: it increased ACSL4‑dependent membrane lipid remodeling and reduced FTH1‑mediated iron sequestration, accompanied by suppression of the antioxidant enzyme GPX4. Consequently, lipid peroxidation, iron overload, and mitochondrial damage were markedly amplified. Notably, knockdown of ACSL4 in SIRT5‑deficient HK‑2 cells effectively reversed lipid peroxidation, iron accumulation, and cell death, establishing ACSL4 as a key downstream effector of SIRT5‑mediated ferroptosis suppression. Our findings reveal a previously unrecognized SIRT5–ACSL4/FTH1 regulatory axis that governs ferroptotic susceptibility in renal tubular cells during sepsis, and suggest that pharmacological restoration of SIRT5 activity or blockade of ACSL4‑driven ferroptosis may offer novel therapeutic avenues for S‑AKI.
SN - 1932-6203
ER -