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Aims/hypothesis: The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes., Methods: SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific Scd1 knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions., Results: SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and db/db mice compared with healthy controls, which was attributed to glucotoxicity-induced Scd1 promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA-HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells., Conclusions/interpretation: Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes., Competing Interests: Data availability: Data will be made available on request. Funding: This study was supported by grants from the National Natural Science Foundation of China (82170810 to FC; 82370803 to TJW; 32171116 and 32371168 to YQZ), the Natural Science Foundation of Jiangsu Province (BK20240132 to TJW), the Project Foundation of Taizhou School of Clinical Medicine affiliated to Nanjing Medical University (TZKY20230310 to MS), the 2023 Taizhou Science and Technology Support Program (Social Development) Project (TS202310 to FC and MS), and the National Key Research and Development Program of China (2022YFF0713005 to DMS). Contribution statement: WYY, SYZ and MS designed and conducted the experiments, analysed data and drafted the manuscript. FC, TJW and YQZ contributed to conception and design of the study, data analysis, collection and assembly of data and manuscript editing. FC, TJW, YQZ, MS and DMS contributed to funding acquisition. DMS, XAC and SSW contributed to interpretation of data and critically revised the manuscript. LJS, HQG, CX, XYH, JNW, YHZ, XRL, JL and WHG participated in data analysis and collection. All authors reviewed and commented on the manuscript. All authors critically revised the paper and approved the final version. FC, TJW and YQZ are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)