To the Editor, Chronic kidney disease (CKD) has become a major health issue, affecting more than 10% of the world population and playing a major role in morbidity and mortality. Regardless of the injurious agent (metabolic, inflammatory, or hemodynamic injury), renal fibrosis is commonly recognized as the ultimate common pathological pathway of the development of CKD1. It entails a gradual deposition of extracellular matrix in the renal interstitium, a sequence of tubular atrophy, glomerulosclerosis, and vascular rarefaction, which eventually results in the irreversible loss of kidney function2. The sustained activation of matrix-producing myofibroblasts, which secrete high levels of collagen and other extracellular matrix proteins that disrupt normal renal architecture, is a central driver of fibrotic remodeling. Although significant progress has been made in elucidating the molecular pathways involved in renal fibrogenesis, existing therapeutic approaches primarily slow disease progression rather than reverse established fibrotic damage, and no effective antifibrotic treatment of CKD is currently available. Consequently, identifying the mechanism responsible for the persistence of fibrogenic cell activation remains a critical priority in nephrology research1,2. A critical cellular event driving renal fibrosis involves the conversion of resident fibroblasts into activated myofibroblasts, which are specialized cells that produce excessive extracellular matrix and tissue scarring. This process is mediated by profibrotic signaling pathways and the sustained transcriptional reprogramming in the injured kidney microenvironment and is known as the fibroblast-to-myofibroblast transition3. There is increasing evidence that such persistent phenotypic modifications are being perpetuated by epigenetic memory, a phenomenon where the signals caused by environmental or injury-induced stimuli cause long-term stable changes in gene expression without any change in the underlying DNA sequence. Key mechanisms underlying this memory are chromatin remodeling, DNA methylation, and histone modifications that regulate the availability of profibrotic genes and strengthen the myofibroblast activation programs4. Notably, these epigenetic marks are capable of persisting even after the injury has resolved, with the subsequent result of fibroblasts maintaining a stable profibrotic transcriptional identity, facilitating continued matrix deposition and progressive fibrosis. Understanding how these epigenetic processes are able to maintain fibroblast activation is therefore essential for developing strategies capable of reversing fibrotic cell states. Recent advances in epigenome engineering indicate that CRISPR-based tools may offer new opportunities to modulate fibrotic cell states without manipulating genomic DNA sequences. Unlike conventional CRISPR-Cas9 nucleases that introduce double-strand breaks, the catalytically inactive Cas9 (dCas9) functions as a programmable DNA-binding scaffold that can be fused to an epigenetic effector domain to regulate gene expression without cutting DNA5. CRISPR-dCas9 systems have the capacity to regulate transcription by targeting chromatin remodeling, DNA methylation changes, or histone modification editing by guiding these effector complexes to particular regulatory sites5,6. Although the majority of antifibrotic methods that are currently in use are oriented toward blocking either an isolated signaling pathway or an individual gene, these methods might not be able to combat the stable transcriptional programs that maintain myofibroblast activation. In that regard, multiplex epigenetic regulation with dCas9-based platforms can permit coordinated fibrotic gene networks rewriting, which can reprogram activated fibroblasts to a more quiescent state and restore tissue homeostasis7. In CRISPR-dCas9 epigenome editing, efficient and safe delivery systems, such as viral vectors, such as Adeno-associated virus vectors (AAV) and lipid nanoparticles (LNP), are required to target and modulate pathogenic transcription programs in renal fibroblasts. AAV have demonstrated promising therapeutic outcomes in the clinical management of renal diseases. This has been demonstrated in murine and in live human kidney using ex vivo normothermic perfusion. They improve capsid configurations and enable gene delivery to renal tubular cells after systemic administration, thus making them feasible for clinical use8. LNPs have been demonstrated to be useful vectors to carry nucleic acid therapeutics; the clinical success of Patisiran (Onpattro) in Amyloidosis highlights the clinical feasibility of LNP-based delivery vectors, which can also be utilized to deliver nucleic acid therapeutics to treat renal fibrosis. LNPs are produced using microfluidic mixing techniques, making them suitable for large-scale pharmaceutical production9. CRISPR-Cas-based systems have shown good outcomes in both clinical and preclinical studies; however, their use is limited due to off-target effects and the absence of standardized guidelines10. Hence, gene therapies and genome-editing tools provide efficient and long-term potential for the control of disease progression. However, appropriate attention to the targeted RNAs and editing systems is essential to ensure the safety and efficacy of these approaches. Remaining challenges, including precise delivery, possible off-target effects, and limited reversibility, should be addressed to enable broader clinical use in the future. To conclude, renal fibrosis can be better understood not simply as being the result of ongoing profibrotic signaling but as a condition that is driven by persistent epigenetic alteration. These changes allow fibroblasts to maintain a stable disease-associated phenotype even after the original injury has resolved, thereby maintaining fibrotic activity to perpetuate the progression of kidney damage. This perspective alters the therapeutic approach from the blocking of individual signaling cascades to reprogramming the cellular identity. New technologies, including the use of epigenome editors CRISPR-dCas9, have the potential to give us a framework to conceptually rewrite maladaptive transcriptional programs to possibly restore fibroblasts to a quiescent state. However, the paradigm is currently rather theoretical, and it must be well tested in preclinical tests, with specific targeting regimes, effective delivery mechanisms, and caution when evaluating safety and off-target results. If these challenges are overcome, epigenetic identity reprogramming may be among the groundbreaking solutions in the sphere of antifibrotic treatment. Although in its infancy, this approach provokes a more basic reconsideration of the biology of fibrosis and offers a tentative but encouraging direction in the future of the disease-modifying interventions of CKD. This is in line with the TITAN Guidelines on the need for transparency in AI use in healthcare11.
Memon et al. (Tue,) studied this question.