Enhancer profiling identifies RXRα as a key suppressor of nephrolithiasis-promoting genes in calcium oxalate kidney stone disease

Abstract During the formation of kidney stones, the interaction between stone crystals and tubular epithelial cells (TECs) leads to tubular injury and dysfunction, triggering osteogenic transformation and inflammatory responses. However, the molecular mechanisms underlying these changes in TECs remain elusive. Through high-throughput drug screening, we identified JQ1, an enhancer targeting epigenetic drug, effectively inhibiting the adhesion of calcium oxalate (CaOx) crystals to primary TECs. We further confirmed its therapeutic effect in a glyoxylic acid-induced CaOx nephrolithiasis mouse model. Utilizing comprehensive epigenomic and transcriptomic profiling, we charted dynamic enhancer landscape and gene expression program associated with nephrolithiasis. An integrative bioinformatic analysis uncovered a transcription factor (TF) regulatory network within TECs, pinpointing the nuclear receptor RXRα as a central TF modulating enhancer activity. Importantly, our animal studies revealed that tubular-specific RXRα deletion promoted kidney stone formation, while its activation by Bexarotene (Bex), an FDA-approved drug, mitigated this progression. Mechanistically, under normal circumstances, RXRα inhibited nephrolithiasis-promoting genes by recruiting the HDAC3/SMART transcription suppressor complex to repress enhancer activity. Yet, with the progression of nephrolithiasis, RXRα expression decreased, leading to enhancer activation and subsequent upregulation of nephrolithiasis-promoting genes. Activation of RXRα by Bex suppressed these genes by reprogramming their enhancer profiles. In summary, our work illustrates an epigenetic mechanism underlying TECs fate transition during kidney stone formation and highlights the therapeutic potential of JQ1-mediated enhancer inhibition and Bex-induced RXRα activation in nephrolithiasis management.