USP1 protein controlling autophagy in cells.

Unlocking Autophagy: How a Key Protein Target Could Revolutionize Cancer Treatment

Avery Sinclair in Health & Wellness December 2025 • 4 min read.

"Scientists identify USP1 as a critical regulator of autophagy, opening new avenues for targeted cancer therapies."

In the relentless battle against cancer, scientists are constantly seeking new vulnerabilities within cancer cells to exploit. One promising area of research is autophagy, a cellular "self-eating" process that, paradoxically, can help cancer cells survive under stress. New research has identified a key protein, USP1, as a critical regulator of this process, offering a potential new target for cancer therapies.

Autophagy, or macroautophagy, is a fundamental process where cells degrade and recycle their own components. It acts like a cellular cleaning service, removing damaged proteins and organelles. While it can be a protective mechanism, cancer cells often hijack autophagy to survive harsh conditions, such as nutrient deprivation or chemotherapy. By understanding how autophagy is regulated, researchers hope to develop strategies to disrupt this survival mechanism and make cancer cells more vulnerable.

The new study, led by researchers at L.N.C.I.B. Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie and the University of Udine, Italy, sheds light on the role of USP1 (ubiquitin-specific peptidase 1) in regulating autophagy. Their findings reveal that USP1 targets ULK1, a key protein involved in initiating autophagy, and regulates its activity and location within the cell. This discovery opens up exciting possibilities for developing targeted therapies that disrupt autophagy and enhance the effectiveness of existing cancer treatments.

What is USP1 and How Does It Control Autophagy?

USP1 protein controlling autophagy in cells.

USP1 is an enzyme known as a deubiquitinase (DUB). DUBs are responsible for removing ubiquitin tags from proteins. Ubiquitination is a process that modifies proteins, affecting their function, location, or stability. By removing ubiquitin tags, USP1 can reverse these modifications and alter the behavior of its target proteins. Previous research has linked USP1 to DNA repair processes, making it an attractive target for cancer therapy.

The new study reveals that USP1 specifically targets ULK1, a protein kinase that plays a central role in initiating autophagy. The researchers found that USP1 removes K63-linked ubiquitin chains from ULK1. This type of ubiquitination is known to affect protein stability, protein-protein interactions, and localization of ULK1, ultimately impacting the cell's ability to perform autophagy.

USP1 Depletion: When USP1 is depleted, ULK1 becomes less soluble in cells and accumulates in specific compartments.
Pimozide Inhibition: Pimozide, an USP1 inhibitor, leads to similar effects, suggesting that USP1 activity is crucial for maintaining ULK1 function and location.
SQSTM1 Interaction: ULK1 interacts with SQSTM1, a protein involved in selective autophagy, indicating a connection between USP1, ULK1, and the targeted degradation of specific cellular components.

The study also found that when USP1 is inhibited or depleted, cells struggle to perform canonical autophagy (the typical form of autophagy). Instead, they shift towards non-canonical autophagy, an alternative pathway that may not be as effective in promoting cell survival. This shift highlights USP1's role in fine-tuning the autophagy process and suggests that targeting USP1 could disrupt the carefully orchestrated balance that cancer cells rely on.

The Future of Cancer Therapy: Targeting USP1

These findings suggest that USP1 could be a valuable target for cancer therapy, particularly in tumors that rely heavily on autophagy for survival. By inhibiting USP1, researchers aim to disrupt autophagy, making cancer cells more vulnerable to traditional treatments. The study provides evidence that the USP1 inhibitor pimozide can affect breast cancer cell growth, suggesting a potential therapeutic strategy.

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Everything You Need To Know

What exactly is autophagy, and why is it significant in the context of cancer?

Autophagy, also known as macroautophagy, is a fundamental cellular process where cells degrade and recycle their own components, acting as a cellular cleaning service by removing damaged proteins and organelles. In the context of cancer, autophagy is significant because cancer cells often hijack this process to survive harsh conditions such as nutrient deprivation or chemotherapy. By understanding how autophagy is regulated, researchers aim to disrupt this survival mechanism, making cancer cells more vulnerable. This is where the protein USP1 comes into play.

How does USP1 influence the autophagy process, and why is this important for potential cancer treatments?

USP1, or ubiquitin-specific peptidase 1, influences autophagy by targeting ULK1, a key protein involved in initiating autophagy. USP1 removes K63-linked ubiquitin chains from ULK1, affecting its stability, protein-protein interactions, and location within the cell, ultimately impacting the cell's ability to perform autophagy. This is important for potential cancer treatments because by inhibiting USP1, researchers aim to disrupt autophagy, making cancer cells more vulnerable to traditional treatments. The shift from canonical to non-canonical autophagy when USP1 is inhibited further highlights its role in fine-tuning the autophagy process.

What is the role of ULK1 in autophagy, and how does USP1 affect its function?

ULK1 is a protein kinase that plays a central role in initiating autophagy. USP1 affects its function by removing K63-linked ubiquitin chains from it. This deubiquitination process impacts ULK1's stability, protein-protein interactions, and localization within the cell. When USP1 is depleted or inhibited, ULK1 becomes less soluble and accumulates in specific compartments, affecting the cell's ability to perform canonical autophagy.

What is the significance of the interaction between ULK1 and SQSTM1 in the context of USP1's role in autophagy?

The interaction between ULK1 and SQSTM1 is significant because SQSTM1 is a protein involved in selective autophagy, the targeted degradation of specific cellular components. This interaction indicates a connection between USP1, ULK1, and the selective autophagy process. By influencing ULK1's function and location, USP1 indirectly affects the targeted degradation of specific cellular components via SQSTM1, further highlighting its role in fine-tuning the autophagy process.

The study mentions Pimozide. What is Pimozide's role in USP1 inhibition and how does it relate to potential cancer therapies?

Pimozide is an USP1 inhibitor. When Pimozide inhibits USP1, it leads to effects similar to USP1 depletion, suggesting that USP1 activity is crucial for maintaining ULK1 function and location. By inhibiting USP1 with Pimozide, researchers aim to disrupt autophagy, making cancer cells more vulnerable to traditional treatments, and the study provides evidence that Pimozide can affect breast cancer cell growth, suggesting a potential therapeutic strategy. However, it's important to note that further research is needed to fully understand its efficacy and potential side effects in cancer treatment.