Transcriptomics-driven drug screening identifies BRD-K78062244 in promoting white adipose tissue browning

Obesity and its related comorbidities have become increasingly challenging in public health globally, and white adipose tissue (WAT) browning enhances energy expenditure and provides a promising therapeutic strategy for treating obesity. However, few drugs have been clinically approved for promoting WAT browning largely due to the involvement of complex signaling pathways, which limits the application of traditional drug screening approaches. Thus, a cross-species gene set that marks the adipose browning process was constructed, and a systematic strategy for compound screening was developed. By integrating single-nucleus and bulk RNA sequencing data from both humans and mice, we established a signature gene set named "white adipose tissue browning-associated gene" (WAT-BAG) through differential gene expression analysis. Candidate compounds were identified by integrating the WAT-BAG gene set with the Connectivity Map (CMap) database, followed by functional validation both in vitro and in vivo. Among the candidates, BRD-K78062244 was ranked as a top compound that induced transcriptional changes resembling the WAT-to-BAT transition. Further analysis revealed that BRD-K78062244 activated the PPAR signaling pathway and inhibited lipid droplet accumulation in adipocytes in vitro. Moreover, intra-inguinal injection of BRD-K78062244 enhanced glucose handling capacity in lean adult mice, accompanied by transcriptomic evidence of enhanced thermogenesis and suppression of lipogenic programs in adipose tissue. This study introduces a transcriptome-guided drug screening strategy that overcomes the limitations of conventional single-target approaches and highlights the potential of BRD-K78062244 in metabolic remodeling. Our findings offer a new framework for identifying compounds that promotes WAT browning via multi-omics-derived gene signatures.