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How metabolic dysregulation promotes polycystic kidney diseases (PKD) remains largely unknown highlighting a critical gap in our understanding of disease pathogenesis. Our recent findings underscore this uncertainty and the urgent need to define the metabolic drivers of PKD. For example, we discovered that uncoupling protein 1 (UCP1), which is a key regulator of thermogenesis in brown fat, is unexpectedly expressed in renal tubular epithelial cells (TECs) of the kidney collecting duct, a hotspot for renal cystic disease origin. While UCP1’s canonical role is to uncouple respiration for heat production, we propose that in renal TECs, it serves a distinct function in mitigating metabolic stress by modulating the mitochondrial electron transport system. This discovery could provide crucial insight into why the collecting duct is particularly vulnerable to kidney disease. However, current single-cell studies have failed to capture these UCP1-positive TECs and other elusive kidney cell populations and lack the spatial resolution needed to map the kidney’s complex metabolic landscape. Compounding this knowledge gap, we found that activation of the TFEB transcription factor may promote cystogenesis upstream of mTORC1 in PKD, establishing TFEB as the key driver and redefining the role of mTORC1 and rapamycin as a potential treatment. Given TFEB’s influence over metabolism, this also suggests that ADPKD is fundamentally a disease of metabolic dysfunction, which is critically underexplored. Building on these discoveries and to fill critical knowledge gaps, we will employ cutting-edge MALDI imaging spatial metabolomics integrated with spatial transcriptomics to map kidney cell metabolism in normal and polycystic kidneys with unprecedented depth. This innovative approach will allow us to chart the transcriptional signatures, metabolic states, and adaptive responses of every kidney cell population, including UCP1-positive TECs, with 3D spatial precision. By capturing metabolic dynamics at single-cell resolution within the native tissue architecture, this work will reveal pathological metabolic shifts in TECs, uncover mechanisms of metabolic crosstalk between TECs and interstitial cells that drive disease progression, and establish ADPKD, fundamentally, as a metabolic disorder. We hope that this high risk-high reward strategy will redefine our understanding of kidney disease and pave the way for novel therapeutic interventions targeting metabolic vulnerabilities in ADPKD.
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