The multifaceted role of PUMA in cell death pathways: its therapeutic potential across cancer types

Cell death is a fundamental process essential to all living organisms, with apoptosis serving as one of the most crucial pathways across various stages of life. Dysregulation of apoptosis is closely associated with numerous diseases, particularly cancer. PUMA (p53 upregulated modulator of apoptosis) is a key mediator of apoptotic cell death. It is activated in response to a wide range of internal and external signals. Beyond its established role in apoptosis, PUMA also regulates other forms of cell death, including necroptosis, autophagy, and ferroptosis, underscoring its critical role in cancer cell death, especially during chemotherapy. However, PUMA activation is frequently impaired in many cancers, leading to resistance to cell death and treatment failure. This review highlights recent advancements in understanding the regulation of PUMA expression at multiple levels, including epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms. It also examines the influence of diverse cellular regulators, such as epigenetic modifiers, transcription factors, non-coding RNAs, kinases, and ubiquitin ligases in modulating PUMA activity. Additionally, we discuss PUMA's role in cancer progression, its impact on the effectiveness of anti-cancer therapies, and its potential as a prognostic biomarker for therapeutic resistance. Finally, we propose critical questions to inspire future research, aiming to deepen the understanding of PUMA regulation and its significance in cancer therapy.