The intricate relationship between ubiquitin-specific proteases (USPs) and programmed cell death (PCD) in breast cancer has emerged as a critical area of research. This review delves into how USPs influence various forms of PCD, including apoptosis, autophagy, ferroptosis, and pyroptosis, which are essential for both tumor suppression and progression. Despite significant advancements in breast cancer treatment, challenges such as drug resistance and metastasis persist. By exploring the dual role of USPs in regulating these pathways, this article highlights potential therapeutic strategies that could enhance treatment efficacy and overcome current obstacles.

The ubiquitin-proteasome system (UPS) is fundamental to cellular homeostasis, orchestrating the fate of multiple cell death pathways. In breast cancer, USPs play a pivotal role by selectively modulating proteins involved in apoptosis, autophagy, necroptosis, ferroptosis, and pyroptosis. For instance, apoptosis, often linked with tumor suppression, can be influenced by USPs like USP22 and USP7, which regulate key proteins such as c-Myc and p53. These proteases can either promote or inhibit cancer cell survival, depending on the context. Moreover, autophagy, a process of cellular self-digestion, exhibits a paradoxical role in breast cancer, sometimes acting as a protective mechanism and at other times promoting tumor growth. USP8 and USP13 have been identified as crucial regulators of Beclin1 and p62/SQSTM1, affecting autophagic processes and potentially influencing therapeutic outcomes.

Emerging non-apoptotic PCD pathways, such as ferroptosis and pyroptosis, offer new avenues for cancer therapy. Ferroptosis, characterized by iron-dependent cell death, holds promise for treating triple-negative breast cancer (TNBC). USP7 and USP35 have been found to regulate ferroptosis, suggesting that manipulating iron metabolism and oxidative stress could provide novel therapeutic approaches. Pyroptosis, an inflammatory form of cell death, also plays a vital role in immune responses and tumor suppression. Proteins like USP48 and gasdermin E (GSDME) contribute to this pathway, further emphasizing the importance of understanding USP interactions in PCD mechanisms.

Beyond their impact on PCD, USPs are also implicated in tumor metastasis and drug resistance, presenting both challenges and opportunities for targeted therapies. The review underscores the need for deeper investigation into the interplay between USPs and less understood PCD mechanisms, such as necroptosis and anoikis, which are crucial for breast cancer progression. By elucidating these complex interactions, researchers aim to develop innovative therapeutic strategies that can effectively address the multifaceted nature of breast cancer.

In conclusion, the intricate regulation of cell death pathways by USPs in breast cancer reveals a promising frontier for developing more effective treatments. Understanding how USPs influence apoptosis, autophagy, ferroptosis, and pyroptosis provides valuable insights into overcoming drug resistance and enhancing therapeutic outcomes. This knowledge paves the way for novel interventions that could revolutionize breast cancer management.