Kidney Week

Abstract: FR-PO0359

Colistin-Induced AKI Is Driven by Maladaptive TFEB Hyperactivation and Rescued by Ultrasmall Copper Nanoparticles

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

• Yoon, Se-Hee, Konyang University Hospital, Daejeon, Korea (the Republic of)

Se-Hee Yoon, MD, PhD

• Choi, YunSeok, Konyang University Hospital, Daejeon, Korea (the Republic of)

YunSeok Choi, MS

• Hong, Sang-Eun, Hannam University College of Life Science and Nano Technology, Daejeon, Korea (the Republic of)

Sang-Eun Hong

• Kim, Eun Kyung, Konyang University Hospital, Daejeon, Korea (the Republic of)

Eun Kyung Kim, PhD

• Lee, Ji won, Konyang University Hospital, Daejeon, Korea (the Republic of)

Ji won Lee, MD

• Park, Yohan, Konyang University Hospital, Daejeon, Korea (the Republic of)

Yohan Park, MD

• Hwang, Won Min, Konyang University Hospital, Daejeon, Korea (the Republic of)

Won Min Hwang, MD, PhD

• Yun, Sung-Ro, Konyang University Hospital, Daejeon, Korea (the Republic of)

Sung-Ro Yun, MD, PhD

• Yoon, Kukro, Hannam University College of Life Science and Nano Technology, Daejeon, Korea (the Republic of)

Kukro Yoon

Background

Colistin nephrotoxicity limits use of this last-resort antibiotic against multidrug-resistant Gram-negative infections, and no targeted therapy exists. Upstream signals driving tubular injury remain undefined. We hypothesized that colistin causes maladaptive hyperactivation of transcription factor EB (TFEB) via AKT/GSK3β/mTOR dysregulation, and that ultrasmall copper nanoparticles (Cu NPs) restore this checkpoint beyond ROS scavenging.

Methods

Ultrasmall Cu NPs (4–6 nm; mixed Cu⁰/Cu₂O) were synthesized by green L-ascorbic acid reduction. Colistin-treated HK-2 cells underwent MTT, Western blot, immunofluorescence, and pharmacologic/genetic perturbations (MK2206, GSK3β-CA, MSL-7, NAC). A murine AKI model (colistin 30 mg/kg/day ± Cu NPs 250 μg/kg; n=6/group) was assessed by PAS/TUNEL, confocal TFEB and LC3B imaging, and ICP-MS.

Results

Colistin suppressed inhibitory phosphorylation of AKT and GSK3β(Ser9) and reduced p-mTOR, driving aberrant TFEB nuclear accumulation, autophagy–lysosome uncoupling, and apoptosis. Cu NPs restored AKT/GSK3β/mTOR signaling, normalized TFEB shuttling, and rebalanced autophagic flux. NAC matched Cu NPs in ROS scavenging but failed to restore signaling or viability, and MSL-7 (TFEB activator) alone was not cytoprotective—indicating signaling restoration, not antioxidant activity, underlies protection. In vivo, Cu NPs attenuated tubular degeneration and TUNEL positivity (P<0.01), normalized renal TFEB and LC3B, and showed prominent renal accumulation.

Conclusion

Pathological TFEB hyperactivation via AKT/GSK3β/mTOR suppression is a novel driver of colistin nephrotoxicity. Cu NPs confer renoprotection by restoring this checkpoint, positioning them as a mechanistically distinct, low-dose therapy for drug-induced AKI.

Fig 1. Cu NPs attenuate colistin-induced tubular injury. (A) PAS, (B) TUNEL. Groups (n=6): control; Cu NPs 250 μg/kg; colistin 30 mg/kg/day; Cu NPs + colistin. **P<0.01, ***P<0.001 vs control; ##P<0.01 vs colistin.

Funding

• Government Support – Non-U.S.