Re-Analysis of GSE293545 Adipose Primary Adipocytes CUX1 Overexpression

Abstract

The original study sought to elucidate how dysregulated adipogenesis contributes to insulin resistance and type2 diabetes by focusing on the transcription factor CUX1 in primary human adipocytes. We reanalysed the GSE293545 dataset to better understand the downstream regulatory circuitry triggered by CUX1 overex- pression, driven by the recognition that human adipocyte models remain undercharacterised compared with murine systems. Using the ARCHS4 archive we assembled raw expression counts and sample metadata, con- structed an AnnData matrix of proteincoding genes, and performed differential expression with limmavoom to generate a CUX1responsive gene signature. This signature was then interrogated with Enrichr for GO, KEGG, transcription factor, and phenotypic enrichment, and with PerturbSeqr to identify smallmolecule and gene perturbations that mimic or reverse the signature. The analysis revealed that CUX1 overexpression upregulates core carbonmetabolism pathways, including the tricarboxylic acid cycle and glycolysis/gluco- neogenesis, together with copperion import and ascorbate metabolism, signalling an elevated energetic state that is accompanied by enrichment of inflammatory and hypoxic transcription factors such as RELB, STAT3, and HIF1A. Conversely, genes involved in ribosomal function, lipiddroplet disassembly, and lipoprotein lipase activity were repressed, indicating a coordinated suppression of protein synthesis and lipid handling. These findings pinpoint MAPK/PI3KmTOR signaling as a central hub, offering both mechanistic insight into CUX1driven adipogenesis and potential therapeutic leverage points.