Abstract: FR-PO0349
Melatonin Attenuates Sepsis-Associated AKI by Alleviating Aberrant Metabolic Reprogramming Through SIRT3-Mediated Deacetylation of Hypoxia-Inducible Factor (HIF)-1α
Session Information
- AKI: Mechanisms - Metabolism and Repair
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Li, Xiaohua, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Ma, Rui, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Yang, Zhenhua, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Pan, Ling, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
Background
Metabolic reprogramming has been identified as a critical event in the pathogenesis of SA-AKI. Melatonin has been demonstrated to regulate energy metabolism in various organ injury models. However, whether it modulates metabolic reprogramming in SA-AKI and the underlying molecular mechanisms remain elusive.
Methods
In vivo, renal function, histopathological changes, inflammation (F4/80 immunohistochemistry, IL-6 and TNF-α mRNA), apoptosis (TUNEL), and metabolic parameters (WB for key glycolytic and fatty acid oxidation proteins; commercial kits for lactate, free fatty acids, and ATP) were assessed. In vitro, tubular injury markers and inflammatory cytokines (LCN2, IL-6, TNF-α mRNA), apoptosis (flow cytometry), and metabolic parameters were evaluated. Rescue experiments were performed using siRNA-mediated SIRT3 silencing, followed by assessment of the aforementioned metabolic parameters, HIF-1α acetylation (IP), colocalization of KIM-1, HIF-1α with pan-acetylation (multiplex immunofluorescence), and SIRT3-HIF-1α interaction (CO-IP).
Results
The kidney undergoes a metabolic shift from FAO to glycolysis in SA-AKI. In vivo experiment showed that melatonin significantly alleviated renal damage. WB analysis showed that LPS upregulated the expression of key glycolytic proteins (GLUT1, HK2, PFKL, PKM2, and p-PDHA1/PDHA1) and increased lactate levels in renal tissue, concurrently, downregulated key FAO proteins (CPT1A and PPARγ), accompanied by FFA accumulation and reduced ATP production. Melatonin significantly reversed these metabolic abnormalities. Similar results were observed in in-vitro experiments. RNA-seq identified SIRT3 as the most significantly downregulated Sirtuin family member following LPS stimulation. Rescue experiments demonstrated that SIRT3 silencing significantly abrogated the effects of melatonin on metabolic reprogramming. Multiplex immunofluorescence showed melatonin decreased LPS-induced HIF-1α acetylation and its colocalization with pan-acetylation in KIM-1 positive injured tubules. SIRT3 knockdown abrogated melatonin-induced HIF-1α deacetylation and restored HIF-1α protein. Co-IP confirmed direct SIRT3-HIF-1α interaction.
Conclusion
This study identifies a melatonin–SIRT3–HIF-1α deacetylation signaling axis that confers renoprotection in SA-AKI through metabolic remodeling.