NPM3 functions as a lactyltransferase to promote necroptosis in male diabetic cardiomyopathy mice models via FASN transcription modulation

Diabetic cardiomyopathy (DCM) is characterized by diastolic dysfunction, which progresses to heart failure and abnormal electrophysiological changes in patients with diabetes. Lactate-mediated histone lactylation has been implicated in DCM pathogenesis. We investigated the mechanisms by which lactate-mediated histone-H3-lysine-18 lactylation (H3K18la) and H3K27la promote necroptosis in male DCM mice models. Lactate-mediated H3K18la and H3K27la participate in necroptosis via modulating fatty acid synthase (FASN) transcription in DCM. Moreover, Nucleophosmin/nucleoplasmin-3 (NPM3), identified as a lactyltransferase, regulated H3K18la and H3K27la, thereby activating FASN transcription and triggering necroptosis. Furthermore, dihydroartemisinin (DHA) inhibited NPM3 lactyltransferase activity by competing for binding sites between lactate and NPM3. Importantly, DHA treatment reduced the expression of NPM3, H3K18la, H3K27la, and FASN; alleviated necroptosis and cardiac tissue damage; and resolved diastolic dysfunction and ventricular hypertrophy in DCM models. In conclusion, NPM3 acts as a lactyltransferase to modulate FASN transcription, thereby triggering necroptosis. Moreover, inhibiting NPM3-induced histone lactylation via DHA represents an efficacious therapeutic strategy for DCM.