DPCDI: an artificial intelligent-derived indicator interpreting the diagnostic, stratification, and therapeutic implications of druggability programmed cell death in heart failure.

Programmed cell death (PCD) pathways with druggable potential represent a promising but still underexplored frontier in heart failure (HF) research for diagnosis, prognosis, and therapy. To address this gap, we developed a Druggable Programmed Cell Death Index (DPCDI) through an integrative machine learning framework. An optimal combination of Lasso and Random Forest algorithms identified 15 pivotal genes (CALCOCO2, VPS13D, CLU, STAT3, OPTN, UBB, CXCL12, PPP1R15A, ATF4, IVNS1ABP, HMGB2, JAK2, EXOC7, ENO1, TPCN1) for DPCDI construction. Non-negative matrix factorization (NMF) analysis stratified HF patients into two distinct subtypes, with Subtype 2 exhibiting elevated apoptosis and mitophagy activity. Single-cell RNA sequencing revealed dynamic JAK2 and IVNS1ABP expression during cardiomyocyte state transitions, while CXCL12 showed stage-specific regulation in endothelial cells. Mendelian randomization analysis indicated that genetic predisposition to elevated JAK2 and STAT3 expression was associated with reduced HF risk, whereas CXCL12 overexpression increased susceptibility. Experimental validation in HF mouse models confirmed increased Cxcl12 and Jak2 expression and decreased Stat3 levels. Furthermore, knockout of Cxcl12, Jak2, and Stat3 induced HF phenotypes. Molecular docking identified pifithrin-α as a potent ligand for CXCL12 and strophanthidin for STAT3. Collectively, DPCDI provides a comprehensive framework for HF diagnosis, risk stratification, and targeted therapeutic development.