Dear Editor,
We thank Dr. Pirola for the thoughtful editorial commentary on our study [
1]. We appreciate the recognition that hepatic isomiRs represent an important and previously underappreciated layer of regulatory complexity in metabolic dysfunction-associated steatotic liver disease (MASLD) [
2].
A central point emerging from both the editorial and our work is that isomiRs should be viewed as a structured and heterogeneous extension of canonical microRNA biology. In our analyses, the majority of isomiRs within a given family exhibit concordant changes in expression across disease states, consistent with regulation at the level of precursor transcription or processing. This argues against a purely stochastic origin and supports the view that most isomiRs act as quantitative modulators of canonical microRNA activity, as highlighted in the editorial.
However, a subset of isomiRs with 5’ end variations that alter seed sequences display discordant behavior. These isomiRs change target mRNA recognition and impact downstream pathways and biology [
3-
5]. From a systems perspective, these isoforms expand regulatory networks by introducing new edges, even when their absolute abundance is modest.
The importance of qualitative microRNA expression is not unprecedented. Rigoutsos and colleagues previously demonstrated that microRNAs could exhibit qualitative celland tissue-specific expression patterns [
6]. This suggests that microRNAs are important for defining and maintaining cell and tissue-specific biology. Our findings expand this principle further, suggesting that isomiRs can contribute to disease pathogenicity, progression, and heterogeneity within a particular tissue.
In the context of precision medicine, incorporating isomiRs dramatically expands the repertoire of actionable biomarkers beyond the canonical list of 1,917 human microRNAs listed in miRBase v22 [
7]. However, leveraging this information requires sequence-level resolution and careful analytical frameworks capable of distinguishing biologically meaningful variants from technical artefacts. As emphasized in the editorial, rigorous methodological controls, such as accounting for RNA integrity and PCR duplication, are essential for interpretation.
We agree that most isomiRs likely fine-tune canonical microRNA activity rather than act as independent regulators. However, the existence of a minority of isoforms with context-specific behavior suggests a hierarchical model in which quantitative modulation predominates, while qualitative divergence can emerge under specific pathological conditions. Distinguishing between these modes will be important for translating isomiR biology into clinically useful insights. Accordingly, we view the present study as hypothesis-generating. We have initiated targeted screening and functional evaluation of selected isomiRs identified here to better understand their potential roles in MASLD progression, with follow-up studies reported separately.
Although our study focused on MASLD, isomiRs are not restricted to a particular disease or phenotype. Like canonical microRNAs, they are broadly expressed and dynamically regulated. Their relevance may therefore extend to other settings in which patient stratification, treatment response, or adverse event susceptibility are not well understood.
We thank the editors of Clinical and Molecular Hepatology for the opportunity to engage in this dialogue and for highlighting emerging dimensions of non-coding RNA biology. We hope that continued investigation of isomiRs will help refine our understanding of regulatory heterogeneity in MASLD and beyond.
FOOTNOTES
-
Authors’ contribution
DWS, SAH, and AJS wrote the correspondence.
-
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
REFERENCES
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