# Regulation of Liver Fibrosis by Pyruvate Kinase M2 (PKM2)

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2023 · —

## Abstract

We have identified an important and previously unknown role for PKM2 in HSC biology and liver
fibrosis. This work will give us a full mechanistic understanding of how PKM2 regulates hepatic stellate
(HSC) metabolism and activation, and test PKM2-binding new chemical entities for anti-fibrotic activity.
HSC are central to the development of liver fibrosis. There is extensive information on the many
transcriptional changes associated with HSC activation but how these changes are initiated and
regulated is still not well understood. From the work in the current Merit award we have identified a
novel role for pyruvate kinase M2 (PKM2) in nuclear regulation of pro-glycolytic, pro-inflammatory and
pro-reactive oxygen species genes in liver macrophages (LM). HSC, upon activation, are faced with the
same organizational challenges as macrophages and other cells which transition from a quiescent to a
highly proliferative and anabolic state.
Hypothesis: Pyruvate Kinase M2 (PKM2) is a key regulator of liver fibrosis. Aim 1: Identify the
regulatory mechanisms of PKM2 mediated HSC activation. a) Identify the TGF-β1 induced post-
translational modifications (PTM) in PKM2 required for PKM2 nuclear translocation. Test the ability of
Erk 1/2 MAP kinases to phosphorylate key sites of PKM2 and use site specific Flag mutants of PKM2 to
identify which mutations result in loss of nuclear localization. b) Identify the nuclear mechanism of
PKM2 mediated transactivation of HSC activation and fibrotic response.
Aim 2: Identify the HSC intrinsic and extrinsic roles of PKM2 in liver fibrosis. a) Identify the HSC
intrinsic roles of PKM2 in liver fibrosis: Determine the role of PKM2 in regulating HSC metabolic
adaptation and downstream events. b) Identify the role of hepatocyte PKM2 in liver fibrosis: Determine
the role of hepatocyte PKM2 in the production by hepatocytes of TGF-β1 and other cytokines that
regulate the TGF-β1 pathway.
Aim 3: Test the in vivo efficacy of novel PKM2 inhbitors for anti-fibrotic activity. We will test the ability of
TEPP-45, and additional novel PKM2 binders, in preventing and reversing liver fibrosis.
The current work will give us a full mechanistic understanding of how PKM2 in different liver cell
populations regulates HSC activation, and liver fibrosis.

## Key facts

- **NIH application ID:** 10513289
- **Project number:** 5I01BX003259-06
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** WAJAHAT Zafar MEHAL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513289

## Citation

> US National Institutes of Health, RePORTER application 10513289, Regulation of Liver Fibrosis by Pyruvate Kinase M2 (PKM2) (5I01BX003259-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10513289. Licensed CC0.

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