# PHLDA1 is a shared diagnostic and key mediator of inflammatory fibrosis in heart and kidney

## TL;DR

This study identifies PHLDA1 as a shared driver of fibrosis in heart and kidney diseases, offering a potential new target for treatment.

## Contribution

The discovery of PHLDA1 as a key mediator and diagnostic marker of inflammatory fibrosis in both heart and kidney.

## Key findings

- PHLDA1 is upregulated in cardiac M1 macrophages and injured kidney cells during inflammation-driven fibrosis.
- PHLDA1 promotes IL-1β expression and fibrosis through a positive feedback loop involving NF-κB signaling.
- Knockout of PHLDA1 reduces fibrosis in kidney and heart tissues.

## Abstract

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.

Utilizing multi-omics technologies and machine learning algorithms, we performed an integrative analysis of HF and 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.

Single-nucleus RNA sequencing (snRNA-seq) revealed concurrent upregulation of IL-1β 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-1β expression and the knockout of PHLDA1 suppressed NF-κB signaling and renal fibrosis. Administration of IL-1β induced PHLDA1 expression in cardiac fibroblasts and renal PDGFRβ+ cells, suggesting a positive feedback loop that contributes to fibrosis.

In this study, we identified PHLDA1 as a key driver of fibrosis in both the heart and kidney, acting through IL-1β mediated intercellular crosstalk. These findings indicate PHLDA1 as a potential therapeutic candidate for mitigating fibrosis in cardio-renal syndrome.

Diagram illustrating organ injury effects on heart and kidney, showing increased PHLDA1 in M1 macrophages and PTE cells, IL-1β release, fibroblast activation, and the development of cardiac and renal fibrosis. Shared key genes and signaling pathways are noted.