YTHDF3 may be associated with MIRI and CFTR-related changes, with YTHDF3 overexpression aggravating myocardial ischemia-reperfusion injury by reducing CFTR expression, and changes in AMPK signalling also observed.
In the GSE123342 dataset, 5444 differentially expressed mRNAs were identified, with CFTR significantly upregulated in myocardial infarction-associated conditions.
Hub genes identified through WGCNA were mainly enriched in ABC transporters and the AMPK pathway.
In the GSE6381 dataset, both CFTR and YTHDF3 showed differential expression, and ROC analysis showed preliminary group separation.
CFTR was found to be closely related to multiple transcription factors, including TP53, STAT3, and TFAP4.
OGD/OGR treatment in AC16 cells decreased YTHDF3 expression and increased CFTR expression.
YTHDF3 overexpression reduced CFTR expression and aggravated OGD/OGR-induced injury in AC16 cells, while additional CFTR overexpression partly attenuated these changes.
In a rat ischemia-reperfusion model, YTHDF3 overexpression increased myocardial infarct size and impaired cardiac function, whereas CFTR overexpression attenuated the injury associated with YTHDF3 overexpression.
CFTR knockdown aggravated OGD/OGR-induced cellular injury and was associated with changes in AMPK signalling.
This research suggests that two proteins — YTHDF3 and CFTR — play important roles in the heart damage that occurs when blood flow is restored after a heart attack, a process known as myocardial ischemia-reperfusion injury (MIRI). Using large gene expression datasets, the researchers identified CFTR as a notably upregulated gene in this condition and found that it interacts with YTHDF3, a protein involved in regulating how RNA messages are read in cells. When heart cells were deprived of oxygen and glucose and then reoxygenated (mimicking ischemia-reperfusion), YTHDF3 levels fell while CFTR levels rose. When YTHDF3 was artificially increased, CFTR levels dropped and cell damage worsened; adding back CFTR partially reversed this damage. The researchers confirmed these findings in living rats: increasing YTHDF3 enlarged the area of heart damage and worsened heart function, while increasing CFTR protected against this effect. Reducing CFTR also made injury worse and was linked to changes in a key cellular energy-sensing pathway called AMPK signalling. The study also identified several transcription factors — including TP53 and STAT3 — that may regulate CFTR, adding another layer to the regulatory picture. This research suggests that the balance between YTHDF3 and CFTR may influence how much damage the heart sustains during reperfusion therapy, which is the standard treatment for heart attacks. The AMPK pathway connection also points toward known cellular stress-response mechanisms. However, the authors emphasize these are preliminary findings, the exact molecular mechanisms remain to be fully validated, and further research is needed before these targets could be considered for therapeutic development.
Tang B, Zhu C, Wang H, Gao M, Li T. (2026). Potential Relationship Between YTHDF3 and CFTR in Myocardial Ischemia-Reperfusion Injury.. Journal of cellular and molecular medicine. https://doi.org/10.1111/jcmm.71240