# Mechanistic Study of PEG-asparaginase-Induced Liver Injury

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $396,750

## Abstract

Project Summary
PEGylated asparaginase (PEG-ASNase) is one of the main drugs used for the treatment of pediatric acute
lymphoblastic leukemia (ALL). Although PEG-ASNase is safe and effective to treat pediatric ALL, its use in adults
is limited due to dose-limiting liver injury that negatively impacts therapeutic efficacy. Therefore, strategies that
can mitigate the risk of PEG-ASNase liver injury are urgently needed.
Our preliminary data show that (1) our murine model of PEG-ASNase liver injury recapitulates clinical features,
(2) PEG-ASNase activates ATGL, leading to white adipose tissue (WAT) lipolysis and hepatic lipid peroxidation
and apoptosis; (3) PEG-ASNase sensitizes hepatocytes to lipotoxicity; (4) Inhibiting adipocyte ATGL genetically
or pharmacologically protects against PEG-ASNase-induced liver injury; (5) PEG-ASNase induces eIF2α
phosphorylation in WAT and triggers adipocyte lipolysis, which can be attenuated by GCN2 inhibition; (6) PEG-
ASNase induces CTSS expression and activates ERK in WAT; (7) in vivo CTSS inhibition attenuates PEG-
ASNase-induced liver injury and ATGL activation; and (8) RNA-seq analysis identified that the PEG-ASNase-
responsive hepatocyte lipotoxicity is associated with upregulation of Cyp2e1.
Based on these observations, we hypothesize that that (1) PEG-ASNase-induced liver injury is due to ATGL
activation and subsequent WAT lipolysis. (2) Mechanistically, we postulate that PEG-ASNase-driven
WAT lipolysis is dependent on GCN2-mediated p-eIF2α and AAR activation, with CTSS induction by PEG-
ASNase leading to ATGL activation. (3) Additionally, we propose that PEG-ASNase sensitizes
hepatocytes to lipotoxicity by inducing Cyp2e1, leading to elevated ROS production and cell death. We
propose three specific aims to test our hypotheses: 1) To demonstrate that inhibition of ATGL-mediated WAT
lipolysis attenuates PEG-ASNase-induced liver injury; 2) to show that the PEG-ASNase responsive ATGL
activation and liver injury are mediated by GCN2-dependent induction of cathepsin S (CTSS); and 3) to
investigate whether the PEG-ASNase responsive induction of Cyp2e1 sensitizes hepatocytes to lipotoxicity.
The proposed work will identify a novel mechanism of drug-induced liver injury caused by the anti-leukemia drug
PEG-ASNase involving drug-induced activation of ATGL and the onset of adipose tissue lipolysis leading to
hepatic steatosis. The three aims are not interdependent but are logically related with a singular focus on
elucidating the mechanism of PEG-ASNase-induced liver injury. The long-term goal of this project is to identify
approaches leading to the safe use of PEG-ASNase and to extend the therapeutic benefit of PEG-ASNase to
adult ALL patients.

## Key facts

- **NIH application ID:** 10938301
- **Project number:** 1R01DK140079-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Christian Antonio Fernandez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,750
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938301

## Citation

> US National Institutes of Health, RePORTER application 10938301, Mechanistic Study of PEG-asparaginase-Induced Liver Injury (1R01DK140079-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10938301. Licensed CC0.

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