Chronic kidney disease (CKD) is a global health burden, with its progression heavily characterized by irreversible kidney fibrosis. A major driver of this fibrotic scarring is the epithelial-mesenchymal transition (EMT), a process where renal tubular epithelial cells lose their standard properties and acquire highly motile, myofibroblast-like features. While the transcription factor Snail1 (encoded by the SNAI1 gene) is widely recognized as the master switch governing EMT, the intricate molecular networks and downstream proteomic alterations it dictates during fibrosis have largely remained elusive.

This new research, published in Genes & Diseases journal by a team from Mahidol University, investigated the comprehensive proteomic landscape and multifaceted functional mechanisms driven by ectopic SNAI1 overexpression in renal tubular cells.

By establishing stably SNAI1-overexpressed renal tubular cell lines and employing advanced label-free quantitative (LFQ) proteomics, the researchers identified 233 proteins with significantly altered expression levels. Comprehensive bioinformatic enrichment and experimental validations revealed that Snail1's influence extends far beyond traditional EMT regulation. Crucially, the study demonstrated that SNAI1 overexpression triggers a profound cascade of nucleolar stress and aberrant ribosome biogenesis, evidenced by the substantial upregulation of the RNA helicase DDX1, the nucleolar protein nucleophosmin, and an expansion of nucleolar organizer regions (NORs).

Furthermore, morphological and flow cytometry analyses confirmed that these SNAI1-driven proteomic shifts force renal tubular cells into a state of cellular senescence. This senescence was robustly characterized by distinct cellular enlargement, increased internal granularity, and the elevated expression of core senescence and DNA damage markers, notably p21 and γH2AX.

Remarkably, the study also uncovered that Snail1 significantly amplifies the senescence-associated secretory phenotype (SASP), directly promoting the secretion of the matrix-degrading enzyme MMP-9, which accelerates extracellular matrix remodeling and tissue inflammation. Alongside this, the signaling cascade aggressively altered focal adhesion dynamics by upregulating the scaffolding protein paxillin, fundamentally enhancing the cell's migratory and fibrotic capacities.

Collectively, this study expands the functional landscape of SNAI1, positioning Snail1 as a central regulator of proteome-wide reprogramming, nucleolar stress, and cellular aging processes in renal cells.

By integrating proteomics with functional validation, the findings provide new mechanistic insights into kidney fibrosis and identify potential therapeutic targets within Snail1-driven pathways. Targeting these newly uncovered processes may offer innovative strategies to halt or reverse fibrotic kidney disease progression.
 
Reference
Title of Original Paper: Deciphering the impact of SNAI1 gene on renal tubular cell proteome, nucleolar stress, ribosome biogenesis, senescence, DNA damage response, and focal adhesion dynamics

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101926

Funding Information:

The National Research Council of Thailand (NRCT)
Mahidol University (No. N42A650361)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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