# Evaluation of the AMPK-BACH1-NRF2 Axis as a Therapeutic Target for Inherited DCM

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $602,080

## Abstract

Dilated cardiomyopathy (DCM)-associated heart failure is a leading cause of death. About a third of all DCM is
caused by variants in genes controlling heart muscle structure and/or function. Although this information is
improving patient management, it has not yet led to new therapeutics.
This proposal is to evaluate the potential of activating the AMPK-BACH1-NRF2 signaling pathway to treat
inherited forms of DCM. The pathway emerged from an unbiased, high-throughput functional genomics screen
to discover novel therapeutic targets and signaling pathways capable of restoring contractile function in human
induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) harboring DCM-causing mutations. The screen and
subsequent validation experiments revealed that activation of the AMPK-BACH1-NRF2 pathway restored
contractility of multiple patients’ hiPSC-CMs carrying the DCM-causing TNNT2 R173W mutation. The magnitude
of the effect was comparable to CRISPR-mediated correction of the mutation. Importantly, activation of the
pathway had no effect on healthy (isogenic control) hiPSC-CMs, suggesting that the therapeutic response is
specific for the disease context.
Modulation of AMPK, BACH1 and NRF2 have been reported to elicit protective effects in ischemic heart disease
models but these targets are largely unexplored in the context of inherited DCM. The proposed Specific Aims
address critical issues necessary to advance targeting this pathway to treat inherited DCM. AIM 1 explores the
selectivity of pathway activation for restoring contractile function in different forms of inherited DCM, including
disease caused by mutations in myofilament (TNNT2, MYH7 and TTN) and non-myofilament (PLN, RBM20,
LMNA) genes. We expect that the pathway will ameliorate contractile dysfunction in multiple forms of DCM. AIM
2 will define the mechanism(s) of action by identifying specific genes downstream of pathway activation that are
essential to restore contractile function. Our hypothesis is that the pathway converges on a subset of NRF2-
target genes. AIM 3 explores whether activating the pathway restores contractile function by normalizing
metabolic and/or ER/SR stress. Finally, AIM 4 tests whether activating the pathway will mitigate clinical features
of DCM using an established mouse model.
A successful outcome of this project will constitute a mechanism-based approach to treat inherited DCM. The
project uses both human patient iPSC models and mouse transgenic models to integrate human cellular context
with whole organism physiology. The outcome will define mechanism(s) of action that might not only benefit
inherited DCM but also inform the development of novel strategies to treat acquired forms of DCM.

## Key facts

- **NIH application ID:** 10889477
- **Project number:** 1R01HL170080-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MARK MERCOLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $602,080
- **Award type:** 1
- **Project period:** 2024-07-16 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889477

## Citation

> US National Institutes of Health, RePORTER application 10889477, Evaluation of the AMPK-BACH1-NRF2 Axis as a Therapeutic Target for Inherited DCM (1R01HL170080-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10889477. Licensed CC0.

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