Abstract: SA-PO0121
Fatty Acid-Driven Metabolic Reprogramming Impairs Macrophage Efferocytosis in AKI
Session Information
- Top Trainee Posters - 3
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 01:48 PM - 01:54 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Liu, Jun, University of California Davis, Davis, California, United States
- Hsu, Ssu-Wei, University of California Davis, Davis, California, United States
- Chang, So-Yi, University of California Davis, Davis, California, United States
- Vang, John, University of California Davis, Davis, California, United States
- Berton, Jenna Mizuki, University of California Davis, Davis, California, United States
- Chen, Ching-Hsien, University of California Davis, Davis, California, United States
Background
Timely clearance of apoptotic cells by macrophages (efferocytosis) is essential for resolution of inflammation and restoration of tissue homeostasis after acute kidney injury (AKI). However, how the injury-associated microenvironment modulates macrophage efferocytic function remains unclear.
Methods
We used a murine model of ischemia/reperfusion (I/R)-induced AKI to investigate how local metabolic signals regulate macrophage efferocytosis. Single-cell RNA sequencing (scRNA-seq), lipidomic profiling, and biochemical assays were employed to identify transcriptional and signaling changes in kidney macrophages. Functional studies included genetic deletion and peptide inhibition of Regulator of G-protein signaling 1 (RGS1) to evaluate efferocytic capacity and renal repair outcomes.
Results
Following I/R injury, extracellular fatty acids accumulated in the injury-associated microenvironment and suppressed macrophage efferocytosis. scRNA-seq identified a distinct subset of efferocytosis-exhausted macrophages with upregulated Rgs1, induced by fatty acid-activated PPARα signaling. Mechanistically, fatty acids also promoted palmitoylation of RGS1, enhancing its interaction with and inhibition of Rac1, a GTPase essential for actin cytoskeletal remodeling during efferocytosis. Loss of RGS1 restored Rac1 activity and efferocytosis, accelerating resolution of inflammation and recovery of kidney function. A novel peptide that blocks RGS1 palmitoylation similarly enhanced apoptotic cell clearance, suppressed proinflammatory cytokine release, and improved functional recovery in vivo.
Conclusion
These findings reveal a dual mechanism by which fatty acids in the injury-associated microenvironment transcriptionally and post-translationally reprogram macrophages to impair efferocytosis. RGS1 emerges as a critical metabolic checkpoint in AKI, offering a potential therapeutic target to enhance inflammation resolution and tissue repair.