The CFIm25/FDPs axis orchestrates protective mitophagy in macrophages to attenuate myocardial infarction.

Alternative cleavage and polyadenylation (APA) is a major post-transcriptional regulatory mechanism that is frequently dysregulated following myocardial infarction (MI). To investigate its role in post-infarction remodeling, we focused on the APA factor cleavage factor Im 25 kDa subunit (CFIm25). We identified macrophage CFIm25 as a pathological regulator of MI and explored its association with mitochondrial quality control. CFIm25 expression was markedly reduced in macrophages during the early stage of MI. Myeloid-specific CFIm25 knockdown significantly reduced infarct size, attenuated cardiac fibrosis, and improved cardiac function after MI. In vitro, CFIm25 deficiency suppressed pro-inflammatory responses and enhanced mitophagic flux, whereas CFIm25 overexpression abolished these protective effects. Transcriptomic analysis identified farnesyl diphosphate synthase (FDPS) as a key downstream effector associated with CFIm25 deficiency. Although FDPS was not established as a direct APA target, our data support its functional role in mediating the downstream effects of CFIm25 loss. Quantitative proteomic profiling revealed significant enrichment of mitochondria-related pathways, indicating extensive mitochondrial remodeling following CFIm25 depletion. Pharmacological inhibition of FDPS using ibandronate attenuated PINK1/Parkin pathway activation, reduced LC3-II accumulation, and suppressed mitophagy, demonstrating that FDPS is functionally required for CFIm25 deficiency-induced mitophagic responses. Collectively, these findings support a model in which CFIm25 deficiency promotes FDPS-dependent activation of PINK1/Parkin-mediated mitophagy, thereby enhancing mitochondrial quality control and limiting inflammation. This study identifies a previously unrecognized CFIm25/FDPS signaling axis regulating macrophage mitophagy following MI and highlights its potential therapeutic relevance in ischemic heart injury.