PHLDA1 is a shared diagnostic mediator for inflammatory fibrosis in heart and kidney

Background: Inflammation-driven fibrosis represents a common pathological endpoint in both heart failure (HF) and chronic kidney disease (CKD), which together affect over 1 billion people worldwide. Understanding the shared molecular mechanisms by which inflammation contributes to the pathogenesis of HF and CKD is crucial for enabling early diagnosis and guiding the development of broad-spectrum therapeutic strategies. Methods: Utilizing multi-omics technologies and machine learning algorithms, we performed an integrative analysis of HF and chronic kidney disease CKD samples to uncover shared mechanisms underlying inflammation-induced fibrosis. Furthermore, key regulators identified through bioinformatic analysis were experimentally validated using primary cell co-culture assays, gene knockout approaches, and bulk RNA sequencing. Results: Single-nucleus RNA sequencing (snRNA-seq) revealed concurrent upregulation of IL-1ß and Pleckstrin Homology-Like Domain Family A Member 1 (PHLDA1) in both cardiac M1 macrophages and injured proximal tubular epithelial (PTE) cells. PHLDA1 promotes IL-1ß expression and knockout of PHLDA1 suppressed NF-?B signaling and renal fibrosis. Administration of IL-1ß induced PHLDA1 expression in cardiac fibroblasts and renal PDGFRß? cells, suggesting a positive feedback loop that contributes to fibrosis. Conclusions: In this study, we identified PHLDA1 as a key driver of fibrosis in both the heart and kidney, acting through IL-1ß mediated intercellular crosstalk. These findings highlight PHLDA1 as a promising therapeutic target for mitigating fibrosis in cardio-renal syndrome. Overall design: We performed the PHLDA1 knock-out on CD10+ cells to investigate the inflammation level changes.