# Role of CMA failure in NASH progression to Hepatocellular Carcinoma

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $377,250

## Abstract

ABSTRACT
This proposal investigates the contribution of defective maintenance of protein homeostasis (proteostasis) in
the steatotic liver, to the progression to hepatocellular carcinoma (HCC). Disturbances in the systems that
maintain liver proteostasis have been observed in HCC, but the extent to which loss of proteostasis in the
steatotic liver constitutes a risk factor for development of HCC remains unknown. We will focus in chaperone-
mediated autophagy (CMA), a protein quality control system that mediates selective degradation of cytosolic
proteins in lysosomes. Defective CMA in liver leads to hepatosteatosis due to alterations in hepatic glucose
and lipid metabolism and in overall energetics. Our recent studies on the interplay between CMA and
oncogenesis have shown that: (I) CMA has an anti-oncogenic effect since failure of CMA, such as that
observed in aging, diabetes or the steatotic liver, favors malignant transformation, and mice with hepatic CMA
blockage develop spontaneous tumors; (II) CMA is required in transformed cells to sustain tumor growth since:
(i) transformed cells maximally upregulate CMA, (ii) blockage of CMA in transformed cells reduces proliferation
and induces cell death and (iii) blockage of CMA in pre-formed tumors inhibits tumor growth and results in
tumor shrinkage.
We propose that 1) the gradual decline of CMA in the steatotic liver facilitates malignant transformation in the
context of a pro-oncogenic stimulus and that 2) interventions to restore normal CMA activity in the steatotic
liver will prevent or slow down progression to HCC.
To test this hypothesis, we intend to: 1) determine the contribution of CMA failure to oncogenic transformation
in HCC; 2) identify the liver and immune cell type-specific contribution of CMA failure to HCC progression; 3)
evaluate the possible beneficial impact of chemical and genetic upregulation of CMA as a preventive
intervention against NASH to HCC progression.
Significance: This study will elucidate how functional impairment of CMA contributes to liver pathology and if it
increases HCC risk in steatotic liver. Our findings could help in developing new approaches to preserve
steatotic liver homeostasis and function and reduce its risk to HCC.

## Key facts

- **NIH application ID:** 9945282
- **Project number:** 1R01DK124308-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Esperanza Arias-Perez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $377,250
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9945282

## Citation

> US National Institutes of Health, RePORTER application 9945282, Role of CMA failure in NASH progression to Hepatocellular Carcinoma (1R01DK124308-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9945282. Licensed CC0.

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