Adv Sci (Weinh). 2026 Aug 27:e77368. doi: 10.1002/advs.77368. Online ahead of print.
ABSTRACT
Calcific aortic valve disease (CAVD) lacks effective drug therapy. This study integrated human valve transcriptomic datasets and tissue specimens, public single-cell and spatial transcriptomics, primary human valvular interstitial cell (VIC) models, and ApoE-/- mice fed a high-fat diet to define the role of KLF5 in VIC remodeling. KLF5 expression was reduced in calcified human valves and associated with hemodynamic severity; tissue and single-cell analyses localized this reduction to VIC-rich lesions and disease-associated VIC states. In primary VICs, KLF5 overexpression suppressed, whereas KLF5 knockdown enhanced, osteogenic medium-induced inflammatory signaling and mineralization. Systemic AAV-mediated KLF5 overexpression attenuated valve dysfunction, leaflet thickening, mineral deposition, and BMP2 expression in ApoE-/- mice. Mechanistically, KLF5 loss increased cytosolic mtDNA accumulation and activated cGAS-STING and NLRP3-associated signaling, whereas cGAS knockdown reduced downstream signaling and interferon-stimulated gene induction. KLF5 directly activated the BNIP3 promoter and supported BNIP3-mediated mitophagy. BNIP3 knockdown markedly reduced the ability of KLF5 overexpression to preserve mitophagic flux and restrain inflammatory signaling and mineralization, whereas BNIP3 re-expression mitigated the corresponding phenotypes in KLF5-deficient VICs. These findings identify a VIC-centered KLF5-BNIP3 regulatory pathway that supports mitochondrial quality control and limits mtDNA-sensitive sterile inflammation, providing a mechanistic rationale for future therapeutic investigation in CAVD.
PMID:42658612 | DOI:10.1002/advs.77368