Activating Transcription Factor 6α Governs Stress-Adaptive Pancreatic β-Cell Mass Expansion by Coordinating Proliferation and Survival.

Progressive loss of pancreatic β-cell mass (BCM) is a hallmark of type 2 diabetes, yet strategies to preserve or restore BCM remain elusive due to incomplete understanding of the molecular mechanisms governing β-cell proliferation in adults. The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis, but the in vivo role of activating transcription factor 6α (ATF6α), the most recently evolved UPR branch, in β-cell proliferation and survival is unclear. Here, we investigated the role of ATF6α in β-cell adaptation under chronic metabolic and physiological stress. We demonstrated that β-cell-specific ATF6α knockout mice exhibited impaired BCM expansion accompanied by reduced β-cell proliferation and increased apoptosis during high-fat diet feeding and pregnancy, but not under basal conditions. In vitro, ATF6α knockdown suppressed proliferation and enhanced apoptosis in chronically stressed MIN6Akita cells, but not in MIN6 cells, whereas ATF6α overexpression promoted β-cell proliferation. Single-cell transcriptomic analysis further revealed that ATF6α directs proliferative transcriptional states in β-cells under metabolic stress, while its absence diverts cells toward nonproliferative states. Together, these findings establish ATF6α as a coordinating regulator of adaptive β-cell proliferation and survival that supports BCM expansion under sustained stress. ARTICLE HIGHLIGHTS: The role of activating transcription factor 6α (ATF6α) in the stress-adaptive regulation of pancreatic β-cell mass (BCM) in vivo remains incompletely defined. We investigated the role of ATF6α in the regulation of BCM, β-cell proliferation, and survival under sustained stress using in vivo and in vitro models. Loss of ATF6α consistently impaired BCM expansion through reduced β-cell proliferation and increased apoptosis across models. Our findings establish ATF6α as an important regulator of stress-adaptive BCM expansion through coordinating β-cell survival and proliferation under sustained stress.