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USP52 inhibits cell ferroptosis via Hippo-YAP pathway and blocks immunotherapy in colorectal cancer

Jingkai Zhou1, Haihang Nie2, Chenhui Liu3

  • 1Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Provincial Clinical Research Center for Intestinal and Colorectal Diseases, Wuhan, China; Hubei Key Laboratory of Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China; Department of Gastroenterology, Taikang Tongji (Wuhan) Hospital, Wuhan, China.

The Journal of Biological Chemistry
|September 17, 2025
PubMed

Insights

Ubiquitin-specific peptidase 52 (USP52) stabilizes Yes-associated protein (YAP), promoting colorectal cancer (CRC) growth and reducing ferroptosis sensitivity. Targeting USP52 may enhance CRC immunotherapy by boosting ferroptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Colorectal cancer (CRC) is a leading human malignancy requiring better molecular understanding for clinical management.
  • Ferroptosis, a novel iron-dependent cell death pathway, is implicated in cancer, but its role and regulation in CRC are not fully understood.
  • Identifying key regulators of ferroptosis sensitivity in CRC is crucial for developing new therapeutic strategies.

Purpose of the Study:

  • To investigate the role of ubiquitin-specific peptidase 52 (USP52) in the regulation of ferroptosis in colorectal cancer.
  • To elucidate the molecular mechanism by which USP52 influences colorectal cancer progression and ferroptosis sensitivity.
  • To evaluate the therapeutic potential of targeting USP52 in colorectal cancer, particularly in combination with immunotherapy.

Main Methods:

  • Identification of USP52 as a deubiquitinating enzyme for Yes-associated protein (YAP) in CRC cells.
  • In vitro assays to assess the effects of USP52 knockdown on YAP stability, CRC cell proliferation, migration, and invasion.
  • In vivo studies using mouse models to evaluate the impact of USP52 inhibition on tumor growth, immune cell infiltration, and response to anti-PD-L1 immunotherapy.

Main Results:

  • USP52 was identified as a specific deubiquitinase for YAP, stabilizing it by removing K11-linked ubiquitin chains.
  • USP52 knockdown led to decreased YAP protein expression and reduced expression of YAP target genes (CTGF, CYR61).
  • USP52 promoted CRC cell proliferation, migration, and invasion, while decreasing sensitivity to ferroptosis. USP52 inhibition retarded tumor growth, increased CD8+ T-cell infiltration, and enhanced anti-PD-L1 therapy efficacy.

Conclusions:

  • USP52 suppresses ferroptosis in colorectal cancer by stabilizing YAP through the Hippo-YAP signaling pathway.
  • Targeting USP52 represents a promising therapeutic strategy to induce ferroptosis and enhance the efficacy of cancer immunotherapy in CRC.
  • USP52 inhibition could be a valuable approach to overcome resistance to ferroptosis and improve treatment outcomes for colorectal cancer patients.
Keywords:
Hippo/YAP pathwaycolorectal cancerferroptosisimmunotherapyubiquitin specific peptidase

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