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Figure 1. Dual regulatory pathways of programmed cell death in cardiomyocytes mediated by piRNAs. (A) HAAPIR-mediated apoptotic pathway. In response to cellular stress, the piRNA HAAPIR upregulates the expression of the acetyltransferase NAT10. NAT10 catalyzes ac⁴C acetylation on TFEC mRNA, enhancing its stability and translation, leading to increased TFEC protein levels. TFEC, as a transcription factor, subsequently activates the expression of the pro-apoptotic gene BIK, ultimately inducing CA; (B) HNEAP-mediated necroptotic pathway. The piRNA HNEAP promotes the expression of the DNA methyltransferase DNMT1. Elevated DNMT1 levels lead to increased production of the transcription factor ATF7. ATF7 upregulates target genes that suppress the expression of CHMP2A, a key inhibitor of the necroptotic pathway. The loss of CHMP2A inhibition thereby predisposes cardiomyocytes to necroptosis. Created with BioRender.com. (2026) https://BioRender.com/0583atk. piRNAs: Piwi-interacting RNAs; CA: cardiomyocyte apoptosis; AHF: acute heart failure; BIK: BCL2 (B cell lymphoma 2)-interacting killer factor; mRNA: messenger RNA; TFEC: transcription factor EC.