biostudies-literatureRoy GNational Center for Advancing Translational SciencesBLRD VAIndiana UniversityWisconsin Alumni Research FoundationNCATS NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNIA NIH HHSUniversity of Wisconsin-MadisonNational Institutes of HealthNational Institute of General Medical SciencesNational Institute on AgingOffice of the Vice Chancellor for Research and Graduate Education, University of Wisconsin-MadisonNIDDK NIH HHSCongenital Hyperinsulinism InternationalIndiana Clinical and Translational Sciences InstituteNational Cancer InstituteSchool of Medicine, Indiana UniversityAmerican Diabetes AssociationNCI NIH HHSU.S. Department of Veterans AffairsNIGMS NIH HHS115834https://www.ebi.ac.uk/biostudies/studies/S-EPMC12266945biostudies-literatureUnknown44(6)β cells are dysfunctional in type 2 diabetes (T2D) and congenital hyperinsulinism (HI), but the mechanisms linking hypersecretion to β cell failure are poorly understood. Here, we use proteomics and functional assays in human and mouse β cell lines to identify VDAC1 as a target for the small molecule hypersecretion inducer SW016789. By enhancing membrane depolarization, SW016789 acutely increases Ca²⁺ influx, eventually driving β cell dysfunction. Time-course transcriptomics analysis reveals a distinct hypersecretory response signature compared to classical endoplasmic reticulum (ER) stress, highlighting ER-associated degradation (ERAD) as a key adaptive pathway. While SW016789 reduces ERAD substrate OS-9 levels, broader ERAD component changes are limited in cell lines. However,Cell reportsVDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.PMC12266945SCR_014387U54 AG065181R21 CA264339RC2 DK125961P30CA082709UC4 DK098085MDBR-24-19-CHIT32 DK064466IK2 BX0046591R01GM148970P30 DK097512UL1 TR0025297-21-PDF-157R01 DK1015732UC4DK098085P30 CA082709R01 GM1489701R21CA264339U54AG065181UL1TR002529R01 DK102948Rodrigues-Dos-Santos KAttie ADJohnson TSBinns DDEmfinger CHMosley ALOrdonez ATemplin ATKeller MPKuntz RLKwakye MBRichardson TIRoy GMukherjee NTan ZSchueler KLKing GCDoud EHKalwat MAfalseVDAC1 is a target for pharmacologically induced insulin hypersecretion in β cells.β cells are dysfunctional in type 2 diabetes (T2D) and congenital hyperinsulinism (HI), but the mechanisms linking hypersecretion to β cell failure are poorly understood. Here, we use proteomics and functional assays in human and mouse β cell lines to identify VDAC1 as a target for the small molecule hypersecretion inducer SW016789. By enhancing membrane depolarization, SW016789 acutely increases Ca²⁺ influx, eventually driving β cell dysfunction. Time-course transcriptomics analysis reveals a distinct hypersecretory response signature compared to classical endoplasmic reticulum (ER) stress, highlighting ER-associated degradation (ERAD) as a key adaptive pathway. While SW016789 reduces ERAD substrate OS-9 levels, broader ERAD component changes are limited in cell lines. However,2025-01-01T00:00:00Z2025 Jun2026-07-15T14:17:16.178Z2025-08-12T03:04:59.763ZS-EPMC122669454051262410.1016/j.celrep.2025.115834