Tumor suppressor BAP1 emerges as a key regulator of metabolism and cell death in tumors

Abstract

BRCA1-associated protein 1 (BAP1) is a deubiquitinase (DUB) localized in both the nucleus and cytoplasm and is widely recognized as a tumor suppressor. Germline and somatic alterations in BAP1 have been strongly associated with increased susceptibility to diverse cancer types and with adverse clinical outcomes. Although BAP1 is best known for its role in epigenetic regulation, particularly through the modulation of histone H2A monoubiquitination (H2Aub) and gene transcription, accumulating evidence suggests that its functional repertoire extends well beyond these canonical activities. BAP1 is increasingly viewed as a central molecular hub through which fundamental cellular processes are integrated and coordinated via its catalytic activity and dynamic protein interaction networks. In this review, the pleiotropic functions of BAP1 are systematically examined across several biological dimensions, including epigenetic regulation, genomic stability, cellular metabolism, and cell fate determination. Notably, BAP1-mediated regulation is highly context dependent, as cell type, differentiation status and tumor microenvironmental (TME) cues may shape its downstream effects and contribute to heterogeneous biological outcomes. By synthesizing these multidimensional regulatory mechanisms, this review provides an integrated overview of the molecular features and functional roles of BAP1, with particular emphasis on its impacts on the regulation of cell death including apoptosis, ferroptosis and disulfidptosis. Collectively, these insights underscore the evolving understanding of BAP1 biology over the past decade and highlight the need for renewed attention to this critical tumor suppressor and its therapeutic potential in cancer.