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Chaperone-mediated autophagy is a tumor-suppressive mechanism in hepatocellular carcinoma

Khushbu Patel1, Begoña Zapateria1, Alexander J Ledet2

  • 1Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine and The Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Cell Reports
|May 28, 2026
PubMed

Insights

Chaperone-mediated autophagy (CMA) loss promotes liver cancer by impairing cell-type-specific tumor suppression. CMA dysregulation and STAG2 accumulation drive hepatocarcinogenesis, highlighting CMA

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Chaperone-mediated autophagy (CMA) is a vital lysosomal pathway for maintaining proteostasis and adapting to stress.
  • CMA function declines with aging and metabolic diseases, which are risk factors for hepatocellular carcinoma (HCC).

Purpose of the Study:

  • To investigate the cell-type-dependent role of CMA in hepatocellular carcinoma (HCC) development.
  • To identify molecular mechanisms by which CMA loss contributes to hepatocarcinogenesis.

Main Methods:

  • Utilized genetically engineered mouse models with specific deletions of the CMA regulator LAMP2A in hepatocytes or T cells within an MYC-driven, TP53-deficient HCC model.
  • Performed proteomic profiling to identify CMA substrates.
  • Validated findings in human HCC tissues.

Main Results:

  • Hepatocyte-specific CMA loss accelerated early malignant transformation.
  • T cell-specific CMA deficiency initially impaired tumor immunity but later supported tumor growth.
  • Accumulation of STAG2, a cohesin complex component, was observed in CMA-dysregulated hepatocytes and human HCC tissues.
  • STAG2 accumulation was linked to cell cycle dysregulation and increased proliferation.

Conclusions:

  • CMA plays a dual role in suppressing liver tumorigenesis, dependent on both hepatocytes and the immune system.
  • STAG2 is a key CMA-controlled molecule implicated in HCC development.
  • Targeting CMA or STAG2 may offer therapeutic strategies for HCC.
Keywords:
CP: cancerCP: immunologycancercell-type specificityliver diseaselysosomal degradationmalignant transformationproteostasisstromal antigen 2tumor suppression

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