CCN1-mediated stress signaling underlies intrinsic cardiomyocyte dysfunction in spinal muscular atrophy

Cardiac involvement in spinal muscular atrophy (SMA) is increasingly recognized, but its cellular basis remains poorly defined. Using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and engineered heart tissues (EHTs), we identify reduced survival motor neuron (SMN) expression, mitochondrial respiratory defects, and impaired contractility in SMA. Transcriptomic analyses reveal cellular communication network factor 1 (CCN1) as a top upregulated gene in SMA iPSC-CMs, consistent with its enrichment in cardiomyocytes across cardiomyopathies. Exogenous CCN1 exacerbates contractile dysfunction in SMA iPSC-CMs. Proteomic profiling reveals sustained p38/mitogen-activated protein kinase (MAPK) signaling activation, synergistically amplified by CCN1 and TNFα, thereby linking stress signaling to cardiac dysfunction in SMA. Therapeutic intervention with tanshinone IIA suppresses CCN1 expression, attenuates p38 activation, and improves contractile function. Notably, combining tanshinone IIA with risdiplam produces additive benefits in mitochondrial and contractile performance. Together, these findings identify a CCN1-mediated mechanism underlying SMA cardiac dysfunction and support combination strategies integrating SMN-dependent and independent therapies.