Contribution of chaperone-mediated autophagy failure to metabolic dysfunction-associated steatotic liver disease progression

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Albert Einstein College of Medicine $109,652 on September 16, 2025, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate chaperone-mediated autophagy failure in metabolic dysfunction-associated steatotic liver disease progression.

The research examines how chaperone-mediated autophagy, a selective cellular degradation process, contributes to hepatic metabolic regulation and proteostasis, with the hypothesis that CMA failure drives development of metabolic dysfunction-associated steatotic liver disease. The funded work leverages genetically modified mice with CMA deficiencies, a fluorescent CMA activity reporter, and small molecule chemical CMA activators suitable for in vivo use to elucidate CMA's hepatoprotective role and the consequences of CMA failure in liver disease pathology.

Performance occurs in Bronx, New York, with work scheduled to conclude by July 1, 2028.

Abstract

Autophagy, the process of lysosomal degradation of cellular components, is a conserved homeostatic mechanism with crucial roles in the maintenance of protein homeostasis (proteostasis) and in the cellular response to stress through rapid organelle and proteome remodeling. A selective type of autophagy found in mammalian cells, chaperone-mediated autophagy (CMA), facilitates the timely and selective degradation of key soluble, cytosolic proteins involved in processes like the regulation of hepatic metabolism, the cell cycle, cell death, and the cellular stress response. Basal and inducible levels of CMA decline with age, resulting in widespread dysregulation of key cellular processes and aggravation of age-related diseases. Metabolic dysfunction-associated steatotic liver disease (masld) is the most common chronic liver disease in western countries. IT represents the beginning of a spectrum of disease that can lead to hepatocellular carcinoma, the third leading cause of cancer death globally. Progressive forms of masld are now the leading etiology of liver transplantation in hepatocellular carcinoma patients. There is only one FDA-approved drug targeting this pathology, despite its high prevalence and impact. Because of CMA's established roles in the regulation of hepatic metabolism, we hypothesized that CMA failure may result in proteostatic and metabolic alterations that favor the development of masld. This proposal contains exciting data supporting this hypothesis. The studies described leverage several already-established, well-characterized genetically modified mice with deficiencies in CMA and a fluorescent reporter of CMA activity, as well as small molecule chemical activators of CMA suitable for in vivo use. We aim to further elucidate CMA's hepatoprotective role, as well as the consequences of CMA failure and their mechanisms (aim 1), and the impact of pharmacologic CMA upregulation (aim 2) during masld development and progression. This proposal will synergize (via a CO-mentorship) the arias laboratory's expertise in liver physiology and pathobiology and the cuervo laboratory's expertise in CMA to discover previously unknown molecular mechanisms of chronic liver disease. IT may further identify CMA as a novel therapeutic target to prevent liver disease progression. This fellowship funding will enable me to advance toward my goal of becoming an independent physician scientist investigator by strengthening my technical abilities; expanding my background on liver pathophysiology, metabolism, and autophagy; and improving my ability to formulate and test scientific hypotheses in a robust and reproducible manner, as well as my scientific communication and presentation skills. The group of exceptional mentors and collaborators assembled for this application will aid in assuring timely completion of the proposed project and a smooth transition into my clinical training.