Nuclear AGO2 exacerbates heart failure with preserved ejection fraction through myocardial ketogenesis.

Summary

Nuclear (but not cytosolic) AGO2 activates HMGCS2 transcription, driving myocardial ketogenesis and a lipotoxicity–ketone toxicity loop that worsens HFD-induced diastolic dysfunction. Genetic suppression of AGO2 or HMGCS2 protected mice from HFpEF-like phenotypes and identified ATP5MG and UQCR10 as downstream effectors.

Key Findings

• Cardiac AGO2 knockdown attenuated HFD-induced diastolic dysfunction; nuclear AGO2 overexpression exacerbated dysfunction.
• AGO2 directly activated HMGCS2 transcription; knockdown of AGO2 or HMGCS2 protected against HFD-induced dysfunction.
• High-throughput profiling identified ATP5MG and UQCR10 as downstream mediators of β-OHB overproduction; a PKCα–ERK–EGR1–AGO2–HMGCS2 axis was delineated.

Clinical Implications

Although preclinical, targeting AGO2/HMGCS2-driven ketogenesis and β-OHB toxicity may offer novel therapeutics for metabolic HFpEF; β-OHB or pathway components could serve as biomarkers for phenotyping and treatment response.

Limitations

• Preclinical mouse model; human validation of the pathway and translatability remain to be established.
• No clinical pharmacologic inhibition data; off-target metabolic effects of pathway modulation are unknown.

Future Directions

Validate AGO2/HMGCS2 activation and β-OHB signatures in human HFpEF tissue; develop selective nuclear AGO2 modulators or HMGCS2 inhibitors; test metabolic combination therapies.