Cellular landscape with cleaning robots representing USP1 protein for autophagy regulation.

Unlocking Autophagy: How USP1 Could Revolutionize Cancer Therapy

Kai Mendoza in Health & Wellness December 2025 • 4 min read.

"Scientists discover how targeting a specific protein, USP1, can control cellular cleaning processes, offering new hope for treating cancer and other diseases."

Imagine your body's cells as tiny cities, constantly working, building, and producing waste. Just like any city, they need a clean-up crew to remove the trash and recycle valuable materials. This crucial process is called autophagy, a cellular 'self-eating' mechanism where damaged components are broken down and reused. Autophagy is essential for maintaining cellular health, preventing disease, and even influencing how our bodies respond to treatments like cancer therapy.

Scientists have long been fascinated by autophagy and its potential to fight various diseases. Recent studies have focused on understanding the intricate controls that govern this process, identifying key proteins that act as switches and regulators. Among these proteins, Ubiquitin Specific Peptidase 1 (USP1) has emerged as a promising target for manipulating autophagy.

A groundbreaking study published in 'Autophagy' sheds light on how USP1 regulates a core component of autophagy called ULK1. The research unveils that USP1 targets ULK1, influencing its location within the cell and its ability to initiate the autophagy process. This discovery opens up exciting possibilities for developing new therapies that harness the power of autophagy to combat diseases like cancer.

What is USP1 and Why Does It Matter for Autophagy?

Cellular landscape with cleaning robots representing USP1 protein for autophagy regulation.

USP1, or Ubiquitin Specific Peptidase 1, belongs to a family of enzymes called deubiquitinases (DUBs). These enzymes are responsible for removing ubiquitin, a small protein that acts like a tag, marking other proteins for degradation or modification. By removing ubiquitin tags, USP1 can stabilize proteins, change their function, or alter their location within the cell.

In the context of autophagy, USP1's role is particularly intriguing because it targets ULK1, a protein kinase that initiates the autophagy process. ULK1 acts as a central hub, integrating various signals to determine when and how autophagy should occur. The study reveals that USP1 specifically removes K63-linked ubiquitin chains from ULK1, a type of ubiquitin modification that affects protein interactions and signaling.

Location, Location, Location: USP1 influences where ULK1 resides within the cell. When USP1 is depleted or inhibited, ULK1 tends to form aggregates and relocate to specific compartments.
Canonical vs. Non-Canonical Autophagy: USP1 plays a role in determining which type of autophagy occurs. Canonical autophagy is the traditional, well-understood pathway, while non-canonical autophagy involves alternative routes and mechanisms.
Collaboration with SQSTM1: USP1's activity affects the interaction between ULK1 and SQSTM1, a protein that helps to recognize and deliver cargo for degradation during autophagy.

The researchers found that when USP1 is removed, ULK1 becomes more heavily ubiquitinated and forms aggregates. This leads to a shift away from canonical autophagy towards alternative pathways, impacting how cells clear out damaged components. By controlling ULK1's ubiquitination status and location, USP1 acts as a key regulator of autophagy, influencing the cell's ability to maintain cleanliness and respond to stress.

A New Strategy for Cancer Treatment?

The study also highlights the potential for targeting USP1 in cancer therapy. The researchers found that inhibiting USP1 with a drug called pimozide affected the growth of breast cancer cells. This suggests that in tumors where autophagy plays a critical role in survival, targeting USP1 could be a valuable therapeutic strategy. By manipulating autophagy, scientists hope to disrupt cancer cells' ability to adapt and resist treatment, ultimately leading to more effective therapies.

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Everything You Need To Know

What is autophagy and why is it important for cellular health?

Autophagy is the cell's essential 'self-eating' mechanism, akin to a cellular recycling system. It involves the breakdown and reuse of damaged components within the cell. This process is crucial for maintaining cellular health, preventing disease, and influencing the body's response to treatments. Without effective autophagy, cells accumulate damaged parts, leading to dysfunction and potential disease development.

What is the role of USP1 in autophagy, and how does it function within the cell?

USP1 (Ubiquitin Specific Peptidase 1) is a deubiquitinase enzyme that regulates autophagy by targeting the ULK1 protein. USP1 removes ubiquitin tags from ULK1, influencing its location and activity within the cell. By controlling ULK1's ubiquitination status, USP1 influences whether canonical or non-canonical autophagy pathways are activated. This directly impacts how cells clear damaged components and respond to stress. When USP1 is inhibited, ULK1 forms aggregates and the autophagy pathway shifts, highlighting USP1's role as a key autophagy regulator.

How does USP1 influence the location of ULK1, and what are the implications of this?

USP1's activity directly affects the cellular location of ULK1. When USP1 is depleted or inhibited, ULK1 tends to form aggregates and relocate to specific cellular compartments. The implications are significant because ULK1's location affects its ability to initiate autophagy. The movement away from its normal location may hinder its ability to perform its function. By influencing where ULK1 resides, USP1 controls whether the cell can effectively initiate autophagy to maintain cellular cleanliness and respond to stress. This change in location is linked to shifts in autophagy pathways.

How does USP1 interact with SQSTM1, and what is the significance of this interaction?

USP1's activity affects the interaction between ULK1 and SQSTM1. SQSTM1 is a protein that recognizes and delivers cellular cargo for degradation during autophagy. USP1's role in regulating ULK1's ubiquitination status influences how ULK1 and SQSTM1 interact. This interaction is essential for the proper functioning of the autophagy process. By impacting this interaction, USP1 can indirectly affect the efficiency and selectivity of autophagy, influencing which cellular components are targeted for removal and recycling.

How might targeting USP1 lead to new cancer treatments, and what is the underlying rationale?

Targeting USP1 holds promise for cancer therapy because it can manipulate the autophagy process, which is often critical for cancer cell survival and resistance to treatment. The study found that inhibiting USP1 with pimozide affected the growth of breast cancer cells. By manipulating autophagy, scientists aim to disrupt cancer cells' ability to adapt and resist therapies. The rationale is that if USP1 is inhibited, autophagy pathways can be altered, making cancer cells more vulnerable to existing treatments or causing them to self-destruct. This approach could lead to more effective and targeted cancer therapies.