Inflamm Res. 2026 Feb 17;75(1):37. doi: 10.1007/s00011-025-02137-x.
ABSTRACT
BACKGROUND: Acute kidney injury (AKI), characterized by rapid renal dysfunction and high mortality, is critically driven by ferroptosis, an iron-dependent form of cell death. While PTEN-induced kinase 1 (PINK1) and sirtuin 3 (SIRT3) are implicated in mitochondrial homeostasis and ferroptosis regulation, their mechanistic interplay in AKI remains unclear. This study investigated the role of emodin, a natural anthraquinone, in alleviating AKI via SIRT3-mediated PINK1 deacetylation and ferroptosis suppression, focusing on mitochondrial integrity, transferrin (TF) interaction, and redox balance.
MATERIALS AND METHODS: Male C57BL/6 mice (n = 6/group), PINK1⁻/⁻, and SIRT3⁻/⁻ mice were pretreated with emodin (40-160 mg/kg, 3 days) before LPS-induced AKI (15 mg/kg). Human renal tubular HK-2 cells were treated with emodin (10-40 µg/ml) and Erastin (0.4 µM, 24 h). Assays included RNA sequencing, immunoprecipitation-mass spectrometry (IP-MS), histopathology (H&E/PAS/PB-DAB staining), ROS/Fe²⁺/GSH quantification, and immunoblotting. Statistical analysis used ANOVA and Student’s t-test.
RESULTS: Emodin reduced serum creatinine and urea in AKI mice, alongside decreased tubular injury and apoptosis. RNA-seq identified ferroptosis as the central pathway, with emodin upregulating PINK1 expression. IP-MS revealed emodin disrupted PINK1-TF binding via SIRT3-mediated deacetylation, reducing Fe²⁺ accumulation and restoring GPX4 levels. In SIRT3⁻/⁻ and PINK1⁻/⁻ models, emodin’s protective effects were abolished, confirming pathway dependency.
CONCLUSION: Emodin mitigates AKI by activating the SIRT3/PINK1 axis, suppressing ferroptosis through cytoplasmic PINK1 deacetylation and TF interaction disruption. These findings highlight SIRT3/PINK1 as a therapeutic target and emodin as a potential agent for AKI management.
PMID:41703345 | DOI:10.1007/s00011-025-02137-x
