LMNA Haploinsufficiency in Human iPSC-Derived Cardiac Organoids Reveals Early Fibrotic Signaling as a Therapeutically Targetable Process

LMNA mutations are a major cause of dilated cardiomyopathy (DCM), with haploinsufficiency representing a common pathogenic mechanism. Yet the earliest disease-initiating events remain poorly defined. Here, we identify a novel intronic splice-site variant, c.937-1G>A, that disrupts pre-mRNA processing and induces nonsense-mediated mRNA decay, resulting in LMNA haploinsufficiency. Using induced pluripotent stem cells (iPSCs) generated from the patient’s peripheral blood mononuclear cells (PBMCs), we differentiated into self-patterning human cardiac organoids to model early LMNA -DCM in a multicellular human context. Single-nucleus transcriptomics revealed unexpectedly broad remodeling across major cardiac cell types beyond cardiomyocytes. Functionally, LMNA -mutant organoids exhibited impaired contractility, altered calcium handling, and increased arrhythmic activity. These changes were accompanied by early profibrotic activation, including increased reactive oxygen species (ROS), periostin (POSTN) secretion, and CTGF expression. Treatment with the antifibrotic drug nintedanib attenuated this response. Together, these findings show that LMNA haploinsufficiency initiates global pathogenic remodeling at an unexpectedly early developmental stage.