Lanifibranor (IVA-337) - a pan-PPAR agonist suppresses TGF-β ₁ -induced cardiac fibrosis and rescues cardiomyocyte function

Background

Cardiac fibrosis is a hallmark of many cardiovascular diseases, driven by sustained fibroblast activation and excessive extracellular matrix deposition, leading to myocardial stiffening and impaired contractility. Current therapies inadequately address this process. This study evaluated the antifibrotic potential of lanifibranor, a balanced pan-peroxisome proliferator-activated receptors (PPARs) agonist, in TGF-β ₁ -induced cardiac fibrosis.

Methods

Human cardiac microtissues, along with 2D and 3D cardiac fibroblast and cardiomyocyte cultures, were used to assess cell viability, structure, metabolism, contractility, and gene expression.

Results

Lanifibranor reduced TGF-β ₁ -induced fibrosis by limiting fibroblast activation and matrix deposition without affecting viability. In fibroblasts, these effects were associated with partial restoration of mitochondrial respiration and reduced focal adhesion maturation. In cardiac microtissues, lanifibranor improved contraction kinetics, decreased profibrotic transcriptional activity, and preserved bioenergetic homeostasis despite altered nucleotide balance. In cardiomyocytes, treatment normalized contractility and calcium handling while maintaining metabolic stability.

Conclusions

Lanifibranor attenuates TGF-β ₁ -driven cardiac fibrosis by combining antifibrotic effects with metabolic and functional improvements in human models.

Research highlights

• Lanifibranor reduces TGF-β ₁ -induced cardiac fibrosis in human 2D/3D in vitro models.

• Fibroblast activation and ECM deposition induced by TGF-β ₁ decline with lanifibranor.

• Lanifibranor partially restores mitochondrial function in TGF-β ₁ -treated fibroblasts.

• Contractility and cellular bioenergetics recover in TGF-β ₁ -treated cardiomyocytes.

• Contraction recovery and metabolic rewiring occur in TGF-β ₁ /lanifibranor spheroids.