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Figure 2. Opposing regulatory roles of piRNAs in cardiac fibrosis. (A) CFRPI-mediated pro-fibrotic pathway. The piRNA CFRPI (piRNA-000691) targets the 3’UTR of APLN mRNA, inhibiting the translation of the protective peptide APLN. Reduced APLN protein levels lead to activation of the PI3K-AKT-mTOR signaling pathway. This cascade promotes fibroblast proliferation, their differentiation into α-SMA-positive myofibroblasts, and subsequent increased deposition of collagen types I and III (COL I, COL III), driving cardiac fibrosis progression; (B) CFAPIR-mediated anti-fibrotic pathway. The piRNA CFAPIR (DQ765973) exerts an anti-fibrotic effect by competitively binding to the MBNL2 protein. This interaction sequesters MBNL2, thereby releasing the bound P21 protein. Elevated P21 activity suppresses the TGF-β1/SMAD3 signaling pathway. Consequently, fibroblast activation is inhibited, maintaining cells in a quiescent state, which leads to reduced expression of α-SMA, COL I, and COL III, and ultimately decreases collagen deposition. Trend Note: CFRPI expression is low in early-stage HF but increases in late stages, showing an opposite trend to APLN expression. HF: Heart failure; APLN: Apelin; piRNA: piwi-interacting RNAs; PI3K-AKT-mTOR: phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin; α-SMA: alpha-smooth muscle actin; TGF-β1: transforming growth factor-β1; 3’UTR: 3’untranslated region; CFAPIR: cardiacfibrosis associated piRNA; CFRPI: cardiacfibrosis associatedpiRNA; SMAD3: mothers against decapentaplegic homolog 3.