Discovering New Therapies for Kidney Fibrosis

Methyltransferase Like 3 and N6-methyladenosine Modifications as Targets to Treat Fibrosis in the Kidneys

Kidney fibrosis remains a critical therapeutic challenge because of its central role in the progression of CKD toward kidney failure. Despite the identification of key protein effectors of the fibrotic program, their direct inhibition has yielded limited clinical success. These limitations underscore the need for a paradigm shift in the development of antifibrotic strategies. Among these, epitranscriptomic modulation, and particularly RNA methylation, has emerged as a promising approach.

In this context, the methyltransferase like 3 (METTL3) acts as a writer enzyme, catalyzing the addition of N6-methyladenosine (m6A) marks to mRNA. This modification stabilizes and enhances the translation of profibrotic transcripts, such as transforming growth factor beta (TGF-β) and collagen type 1 alpha 1 chain, thereby accelerating CKD progression. Accumulating evidence from human kidney biopsies and experimental models demonstrates that METTL3 upregulation correlates with enhanced fibrogenic signaling, underscoring its potential as a therapeutic target.

In this issue of JASN, Lee et al. identify the heat shock protein inhibitor dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) as a negative regulator of METTL3 and an antifibrotic drug.¹ By applying a transcriptome-based drug repositioning approach, the authors demonstrate that 17-DMAG reduces METTL3 expression, leading to selective changes in m6A methylation, and destabilizes profibrotic mRNAs, ultimately attenuating maladaptive extracellular matrix deposition, a hallmark of CKD. This study provides novel insights into the therapeutic potential of targeting RNA methylation machinery and highlights drug repositioning as a promising therapeutic strategy for kidney fibrosis.

From Epitranscriptomics to Drug Repositioning and CKD Therapy

The complexity of the fibrotic mechanism(s) requires innovative therapy approaches. Manipulating the epitranscriptome machinery offers promising opportunities to halt or reverse the progression of CKD. Epigenetic modifications, including DNA and RNA methylation, are crucial regulators of gene expression in both physiology and pathological conditions and play a crucial role in promoting the fibrotic processes and the progression of kidney disease. In CKD, several epigenetic abnormalities have been identified, including in DNA, RNA, and histone modifications, influencing the expression of genes involved in fibroblast activation, inflammation, and oxidative stress. Targeting these epigenetic modulators, upstream of effector protein translation, could be an alternative strategy to control profibrotic factors. Among these epigenetics modifications, RNA methylation, particularly m6A RNA methylation, represents a prevalent and important layer of gene regulation.^2,3 This dynamic process is mediated by writers (such as METTL3) that add methylation marks, erasers that remove them, and readers that interpret these marks to regulate mRNA translation and degradation.

Compared with targeting DNA methylation, the reversibility of RNA methylation offers a more dynamic and fine-tuned regulation of gene expression at the post-transcriptional level, potentially allowing for a faster and more specific therapeutic effect. Accumulating evidence supports a positive correlation between the expression of the methyltransferase METTL3 writer and the progression of kidney fibrosis. Several studies have reported upregulation of METTL3 expression in human kidney biopsies of patients with CKD as well as in experimental models of AKI and CKD, associated with enhanced activation of profibrotic signaling pathways.^4,5 However, research area on epigenetic and epitranscriptomic changes and alteration in kidney fibrosis is still emerging and remains inconclusive. Thus, identifying regulators of METTL3 expression could offer new therapeutic options to treat fibrosis and CKD.

Identification of 17-DMAG as a Lead Candidate

A central strength of this study lies not only in its mechanistic findings but in the strategy used to identify 17-DMAG as therapy approach. Drug repositioning, the repurposing of compounds with established safety and pharmacokinetic profiles for new indications, offers some important advantages over de novo drug discovery: It dramatically compresses development timelines, substantially reduces costs, and mitigates late-stage attrition by leveraging existing human safety data. In the context of CKD, where the gap between preclinical promise and clinical translation has been repeatedly led to disappointment, this approach is particularly compelling.

Lee et al. used a transcriptome-based drug repositioning approach to identify potential therapeutic candidates for CKD and METTL3 targeting.¹ To this end, the authors developed a robust bioinformatics pipeline: They performed differential gene expression analysis using the GSE66494 dataset, comparing kidney samples from normal versus CKD participants and stratifying groups by METTL3 expression levels. This analysis revealed a strong association between METTL3 and key fibrosis markers, such as actin alpha 2, TGF-β1, and collagen type 1 alpha 1 chain.

By integrating these data with drug–gene interaction profiles from the Library of Integrated Network-Based Cellular Signatures database and applying a reverse enrichment strategy, the authors identified compounds capable of restoring disease-associated gene expression signatures in CKD. After excluding toxic and nonspecific compounds, the HSP90 inhibitor 17-DMAG emerged as the most promising candidate for reversing CKD-related transcriptional signatures.

The authors first validated the effects of 17-DMAG using renal cancer cell lines and an in vitro model of TGF-β–induced fibrosis. They demonstrated that 17-DMAG inhibits METTL3 expression without altering global m6A levels, while selectively reducing m6A modification on specific profibrotic transcripts, such as NET1. Mechanistically, 17-DMAG–mediated HSP90 inhibition activates HSP70, which in turn suppresses the expression of c-Jun, a transcription factor essential for METTL3 transcription. This cascade leads to reduced METTL3 expression and selective remodeling of m6A methylation on fibrosis-related mRNAs, contributing to their destabilization.

The authors then confirmed these findings in preclinical models. In vivo, administration of 17-DMAG in two distinct animal models of kidney fibrosis, unilateral ureteral obstruction and unilateral ischemia-reperfusion injury, resulted in a decrease in METTL3 mRNA expression and m6A levels, as well as alleviated kidney fibrosis. In addition, 17-DMAG induced m6A modifications in the unilateral ischemia-reperfusion injury model, leading to the downregulation of several fibrosis-related and inflammation-related genes.

Overall, by combining a computational approach for drug repurposing and preclinical data, the study provides novel insights into the potential of targeting the RNA methylation machinery as therapeutic strategy for kidney fibrosis. The main conclusions of the study are consistent with the previous work published by authors, already showing that METTL3 inhibition can reduce the development and progression of kidney fibrosis.⁶ However, by identifying 17-DMAG as a regulator of METTL3, the current study provides a link between HSP90, epigenetics, and kidney fibrosis. The authors also provided mechanistic insights into the machinery linking HSP90 status to METTL3 expression. Although the mechanism is extensively characterized, the use of renal carcinoma cell lines is an important limitation because tumor cell lines may not fully recapitulate the pathophysiological environment of fibrotic kidney cells. Cancer-specific signaling pathways, including HSP90-dependent mechanisms, could differ significantly from those in nonmalignant fibrosis. Future validation in renal epithelial cells or, even better, in renal epithelial organoids would strengthen translational relevance.

Chaperone Inhibition and Epitranscriptomic Control

Originally identified as an HSP90 inhibitor,⁷ 17-DMAG now emerges in this study as a promising therapeutic candidate for kidney fibrosis, highlighting the potential of HSP90 inhibition as a novel antifibrotic strategy.

However, given the pleiotropic nature of HSP90, some concerns can be raised regarding the specificity of 17-DMAG and the extent to which the observed effects can be uniquely attributed to METTL3-mediated epitranscriptomic regulation. Indeed, with different mechanisms of action, HSP90 inhibition was already shown to reduce fibrosis in the kidney and other organs.⁸ This, in turn, prompts the question of whether more selective targeting of METTL3 could achieve comparable and/or potentially superior therapeutic benefits while minimizing off-target effects. In the previous study conducted by the authors,⁶ they adopted a targeted strategy with specific METTL3 inhibitor– and small interfering RNA–mediated knockdown and established a direct causal relationship of METTL3 targeting with kidney fibrosis.

By contrast, the use of 17-DMAG reflects a potentially broad-spectrum pharmacological intervention; thereby, in our opinion, this limits the ability to attribute the observed effect to a single molecular, epigenetic target. While long-term safety and tolerability of HSP90/METTL3 inhibition in the context of CKD remain uncertain and to be fully explored, preliminary data and existing clinical experience with 17-DMAG in other diseases are encouraging, supporting the rationale for continued investigation of its therapeutic potential for kidney fibrosis. A clinical trial (NCT07163325) is currently underway to evaluate the safety profile and antitumor activity of targeting METTL3 in patients with advanced solid tumors. This effort may, in the near future, provide a rationale for exploring the therapeutic potential of such approaches in CKD.

Translational Potential

The findings of Lee et al. carry significant translational implications for CKD, a disease in which therapeutic options remain limited. Repurposing 17-DMAG capitalizes on its existing clinical pharmacokinetic and safety dataset, bypassing the early phases of drug development and reducing the timeline to a potential proof-of-concept trial in CKD. The observed preservation of renal blood flow together with the reduced collagen deposition in preclinical models suggest that the 17-DMAG may act on functionally relevant end points, although whether these translate into preserving kidney function in a clinical setting remains to be established.

Conclusion

As our understanding of RNA modifications grows, manipulating the epitranscriptomic machinery may open unprecedented opportunities to halt or even reverse fibrosis and CKD progression. Targeting pivotal layer of epigenetic regulation could be a perfect tool to develop the next generation of antifibrotic therapies. Targeting transcriptional regulators that coordinate profibrotic gene networks may allow for simultaneous attenuation of multiple fibrogenic mediators, offering a more integrated and potentially efficacious intervention.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F825.

Author Contributions

Conceptualization: Lilia Abbad, Christos Chatziantoniou.

Writing – original draft: Lilia Abbad, Christos Chatziantoniou.

Writing – review & editing: Lilia Abbad, Christos Chatziantoniou.

Funding

C. Chatziantoniou: Inserm, Sorbonne Université.