Deubiquitinating enzymes: Key regulators of ferroptosis and pyroptosis and novel targets for cancer intervention.

Most chemotherapeutic drugs are introduced to eliminate tumors by targeting apoptotic cell death, but chemoresistance frequently develops owing to the aberrant apoptotic machinery. Although the emergence of immune checkpoint blockade (ICB) has revolutionized cancer therapeutics, poor responses to ICB and an immunosuppressive tumor microenvironment are commonly observed in solid tumors. Hence, restoring chemosensitivity and immunosurveillance is important for improving patient outcomes. Recently, the induction of nonapoptotic programmed cell death (PCD), such as ferroptosis and pyroptosis, has received much attention since these alternative forms of cell death potentially increase chemosensitivity and augment antitumor immunity. Ubiquitination and deubiquitination are well-recognized posttranslational modifications, and the balance between these processes is important for maintaining cellular homeostasis. Dysregulation of deubiquitinating enzymes (DUBs) is reportedly associated with tumor progression. Additionally, emerging studies have suggested the involvement of DUBs in modulating cellular susceptibility to nonapoptotic PCD. Nevertheless, the crosstalk between DUBs and nonapoptotic PCDs and their implications for cancer treatment have not been thoroughly reviewed. In this review, we elucidate the roles of DUBs in regulating ferroptosis and pyroptosis via their DUB activities or noncanonical functions. Moreover, we thoroughly discuss the challenges and urgent problems associated with targeting DUBs to induce nonapoptotic PCDs as cancer therapeutics.