Scientists Uncover Hidden Protein Driver Behind Scarring Kidney Disease

Chronic kidney disease affects hundreds of millions of people worldwide, and its most destructive feature is often invisible until it is far too advanced: fibrosis, the relentless accumulation of scar tissue that slowly strangles the kidney’s filtering machinery. Once renal tissue becomes fibrotic, the damage is generally considered irreversible, and treatment options remain painfully limited. Now, a team of researchers in China has identified a molecular culprit that appears to sit at the heart of this scarring process, and their findings, published in Cellular and Molecular Life Sciences, point to a surprising connection between a membrane-bound protein, a cellular growth signal, and the cell’s waste-disposal system.

The protein in question is Annexin A1, or ANXA1, a calcium-dependent phospholipid-binding protein that has long been known for its roles in inflammation and membrane dynamics. In the new study, led by Lianqin Sun, Hui Zhang, and Juanjuan Jiang, with corresponding authors Huayong Zhang, Jingfeng Zhu, and Chunming Jiang, the researchers found that ANXA1 is dramatically elevated in the interstitial myofibroblasts of fibrotic kidneys, both in human patients and in rodent models of the disease. Myofibroblasts are the activated, hyperproductive form of fibroblasts, and they are widely regarded as the principal factories of extracellular matrix, the collagen-rich material that accumulates in fibrotic organs.

To understand whether ANXA1 was merely a bystander or an active participant in this process, the team turned to cell culture experiments using renal fibroblasts stimulated with transforming growth factor beta 1, or TGFβ1, the canonical pro-fibrotic cytokine that drives fibroblast activation. When the researchers silenced the Anxa1 gene using small interfering RNA, they observed a striking result: the fibroblasts no longer underwent full activation in response to TGFβ1, and their production of extracellular matrix components, including fibronectin and the fibroblast activation marker alpha-smooth muscle actin, dropped significantly. The same held true in primary renal fibroblasts isolated directly from kidney tissue, strengthening the case that the effect was not an artifact of a single immortalized cell line.

The in vitro findings were then translated into a living system. Using a mouse model of unilateral ureteral obstruction, or UUO, a standard experimental technique in which one ureter is ligated to induce rapid, reproducible kidney fibrosis, the researchers delivered a viral construct carrying a short hairpin RNA against Anxa1, packaged in adeno-associated virus serotype 9, to knock down the protein specifically in fibroblasts. The results were clear: fibrotic marker expression in the obstructed kidneys declined, and abnormal collagen accumulation was visibly alleviated. Supplementary data from the study also indicated that Anxa1 knockdown reduced the inflammatory response, as measured by the abundance of F4/80-positive macrophages infiltrating the fibrotic tissue.

Having established that ANXA1 promotes fibroblast activation, the team dug into the mechanism, and this is where the study becomes particularly intriguing. Through protein interaction analysis, they discovered that ANXA1 physically interacts with YAP, or Yes-associated protein, a transcriptional co-activator famous in cancer and developmental biology as a central effector of the Hippo signaling pathway. When YAP is active, it translocates into the nucleus and switches on genes that drive cell proliferation, survival, and, crucially in this context, fibrotic activation. The researchers found that ANXA1 promotes this nuclear translocation of YAP, effectively amplifying the pro-fibrotic transcriptional program inside activated fibroblasts.

But the story did not end with YAP. The team’s gene enrichment analyses, using Gene Ontology classification of differentially expressed genes from fibroblasts with and without Anxa1 silencing, pointed toward a second, unexpected player: autophagy, the cellular recycling process by which cells digest and reuse their own damaged components. Autophagy has a complicated relationship with fibrosis, and in this study the evidence suggested that ANXA1, through its activation of YAP, suppresses autophagic flux, the throughput of the autophagy machinery, as reflected by altered levels of the lipidated form of the autophagy protein LC3B, known as LC3B II. In other words, ANXA1 appears to jam the fibroblast’s recycling system, and this jamming contributes to the cell’s transition into its matrix-producing, scar-building state.

The mechanistic chain was tested from both ends. When the researchers overexpressed YAP in fibroblasts, LC3B II levels changed in ways consistent with YAP-mediated autophagy retardation, and blocking YAP with the inhibitor verteporfin, referred to as VTP in the supplementary figures, blunted the expression of fibrotic proteins such as fibronectin and alpha-smooth muscle actin after TGFβ1 stimulation. Downstream YAP target genes, including Ctgf and Cyr61, two well-established readouts of YAP transcriptional activity, also shifted across the experimental groups. Conversely, when the team overexpressed ANXA1 and simultaneously boosted autophagy with rapamycin, a drug that activates the autophagy-initiating kinase mTOR pathway in reverse by inhibiting mTOR, fibronectin expression was reduced, confirming that restoring autophagic activity could counteract ANXA1’s pro-fibrotic push.

The pharmacological angle was then extended into the animal model. Rapamycin treatment improved extracellular matrix deposition in UUO-induced fibrotic nephropathy, providing in vivo support for the idea that the autophagy arm of this pathway is not just correlative but functionally relevant. Taken together, the data sketch a coherent signaling axis: ANXA1 binds YAP, YAP enters the nucleus, YAP-driven transcription suppresses autophagic flux, and the resulting cellular state favors fibroblast activation and collagen overproduction. Disrupting any link in this chain, whether by silencing ANXA1, inhibiting YAP, or pharmacologically enhancing autophagy, appears to loosen the fibrotic grip on the kidney.

The clinical implications are worth pausing over. Chronic kidney disease is a growing global burden, driven by rising rates of diabetes, hypertension, and aging populations, and current therapies slow but rarely halt the fibrotic progression that ultimately leads to end-stage renal disease and dialysis dependence. If ANXA1 proves to be a viable drug target, it would offer a way to intervene at an upstream control point that simultaneously governs fibroblast activation, inflammatory cell recruitment, and autophagic regulation. The researchers suggest that targeting ANXA1 may provide a new therapeutic avenue for treating chronic renal disease, and the fact that the pathway can be modulated at multiple nodes, including with an approved drug like rapamycin, gives medicinal chemists and clinicians several potential entry points to explore.

As with any preclinical study, important questions remain before these findings can be translated into treatments. The work relied on the UUO model, which produces rapid fibrosis but does not fully recapitulate the slow, metabolic and hypertensive injury patterns seen in most human chronic kidney disease, and the authors note that the published version is an early-release, peer-reviewed accepted manuscript subject to further edits. Human tissue observations and rodent experiments were conducted under ethics approvals from Nanjing Drum Tower Hospital, and the project was supported by the National Nature Science Foundation of China. Whether ANXA1 levels can serve as a biomarker of fibrotic progression, and whether ANXA1-targeting strategies can be delivered safely to the kidney without disturbing the protein’s roles in inflammation and innate immunity, will be the critical next steps. For now, the study adds a compelling new link to the molecular map of kidney scarring, one that connects an old inflammatory protein to the modern biology of mechanotransduction and cellular self-cleaning, and it does so with a level of mechanistic completeness that makes the pathway a serious candidate for drug development.

Subject of Research: The role of Annexin A1 in regulating YAP-mediated autophagy during fibroblast activation in kidney fibrosis

Article Title: Annexin A1 contributes to fibroblast activation in kidney fibrosis via regulating YAP-mediated autophagy

Article References: Annexin A1 contributes to fibroblast activation in kidney fibrosis via regulating YAP-mediated autophagy. (n.d.). https://doi.org/10.1007/s00018-026-06472-y

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06472-y

Keywords: Annexin A1, kidney fibrosis, chronic kidney disease, fibroblast activation, YAP, autophagy, TGF-beta 1, extracellular matrix, myofibroblasts, rapamycin, unilateral ureteral obstruction, renal fibrosis