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

CCN1 upregulation in SMA patient-specific iPSC-derived cardiomyocytes is linked to worsened contractility, with sustained p38/MAPK stress signaling amplified by CCN1 and TNFα.

• Why it matters: Cardiac involvement in spinal muscular atrophy is recognized, but the cellular mechanism driving cardiomyocyte dysfunction is poorly defined.
• What they did: Using SMA iPSC-CMs and engineered heart tissues, transcriptomics identified CCN1 as a top upregulated gene; exogenous CCN1 worsened contractility, and proteomics showed sustained p38/MAPK activation synergistically amplified by CCN1 and TNFα.
• The result: Tanshinone IIA suppressed CCN1 expression, attenuated p38 activation, and improved contractile function, and combining tanshinone IIA with risdiplam produced additive benefits in mitochondrial and contractile performance.