Inhibition of USP1 Activates ER Stress through Ubi-Protein Aggregation to Induce Autophagy and Apoptosis in HCC
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The deubiquitinating enzyme USP1 (ubiquitin-specific protease 1) plays a role in the progression of various tumors, emerging as a potential therapeutic target. This study aimed to determine the role of USP1 as a therapeutic target in hepatocellular carcinoma (HCC). We detected USP1 expression in the tumor and adjacent tissues of patients with HCC using immunohistochemical staining. We evaluated the effect of the USP1 inhibitor ML-323 on HCC cell proliferation and cell cycle using a CCK-8 cell-counting kit and plate cloning assays, and propidium iodide, respectively. Apoptosis was detected by annexin V-FITC/Propidium Iodide (PI) staining and caspase 3 (casp3) activity. Transmission electron microscopy and LC3B immunofluorescence were used to detect autophagy. Western blotting was used to detect the accumulation of ubiquitinated proteins, the expression of endoplasmic reticulum (ER) stress-related proteins, and the AMPK-ULK1/ATG13 signaling pathway. We demonstrated that ML-323 inhibits the growth of HCC cells and induces G1 phase cell cycle arrest by regulating cyclin expression. ML-323 treatment resulted in the accumulation of ubiquitinated proteins, induced ER stress, and triggered Noxa-dependent apoptosis, which was regulated by the Activating Transcription Factor 4(ATF4). Moreover, active ER stress induces protective autophagy by increasing AMPK phosphorylation; therefore, we inhibited ER stress using 4-Phenylbutyric acid (4-PBA), which resulted in ER stress reduction, apoptosis, and autophagy in ML-323-treated HCC cells. In addition, blocking autophagy using the AMPK inhibitor compound C (CC), chloroquine (CQ), or bafilomycin A1 (BafA1) enhanced the cytotoxic effect of ML-323. Our findings revealed that targeting USP1 may be a potential strategy for the treatment of HCC.
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From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [52]
In male SCID mice subjected to 14 days of restraint stress, there was increased expression of aging markers p16INK4a and p21, alongside reduced DNA damage repair capabilities.
“In a study involving male SCID mice subjected to 14 days of restraint stress, researchers observed an increased expression of aging markers such as p16INK4a and p21, alongside reduced DNA damage repair capabilities.”
From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [52]
Chronic stress can significantly affect biological aging pathways, particularly within bone marrow leukocytes, potentially mediated by sympathetic beta-adrenergic receptor activation.
“The findings suggest that chronic stress can significantly affect biological aging pathways, particularly within bone marrow leukocytes, potentially mediated by sympathetic beta-adrenergic receptor activation.”
From Comprehensive review of chronic stress pathways and the efficacy of behavioral stress reduction programs (BSRPs) in managing diseases. (2024) · cites this paper as [52]
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Shchaslyvyi, A. Y., Antonenko, S. V., & Telegeev, G. D. (2024) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph21081077 · Cited by 73 · see citing works
- Authors
- Wang, L., Hu, T., Shen, Z., Zheng, Y., Geng, Q., Li, L., Sha, B., Li, M., Sun, Y., Guo, Y., Xue, W., Xuan, D., Chen, P., & Zhao, J.
- Affiliations
- Zhengzhou University (CN)
- Corresponding author
- Chen, Ping
- Zhao, Jie
- ORCID
- Venue
- Cell Death & Disease
- Published
- 2022-11-10
- Volume
- 13
- Issue
- 11
- Pages
- 951-951
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC9649627
- OpenAlex
- W4309075680
- Cited by
- 45
- References
- 58
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 14 · 2023: 5
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Natural Science Foundation of Henan Province (202300410460)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- USP1, hepatocellular carcinoma, endoplasmic reticulum stress, autophagy, apoptosis, Noxa, ATF4, AMPK/ULK1 signaling, G1 cell cycle arrest, cyclin expression, 4-phenylbutyric acid, therapeutic target
- MeSH terms
- Autophagy, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Propidium, Apoptosis, Cell Line, Tumor, AMP-Activated Protein Kinases, Ubiquitinated Proteins, Endoplasmic Reticulum Stress, Ubiquitin-Specific Proteases, Protein Aggregates
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