The dual PPAR-α/δ agonist elafibranor attenuates TGF-β 1 -induced cardiac fibrosis through redox-metabolic and bioenergetic reprogramming in human cardiac models

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Abstract Background Cardiac fibrosis drives adverse myocardial remodelling through persistent fibroblast activation, ECM deposition, and impaired cardiac function. Current therapies offer limited protection against cardiac fibrosis progression. Elafibranor is a dual PPAR-α/δ agonist approved for the treatment of liver disease. However, its effects in human models of cardiac fibrosis remain insufficiently explored. Methods Elafibranor was evaluated in complementary human in vitro TGF-β 1 -induced cardiac fibrosis models: 2D primary fibroblasts, 3D fibroblast spheroids, spontaneously contracting 3D cardiac microtissues, and hiPSC-derived cardiomyocytes. Viability, apoptosis, fibroblast activation, ECM remodelling, mitochondrial respiration, nucleotide and NAD pools, calcium handling, contractility, and transcriptomic profiles were assessed. Results At non-cytotoxic concentrations, elafibranor attenuated TGF-β 1 -driven cardiac fibrosis responses. In 2D cardiac fibroblasts, it reduced myofibroblast differentiation, procollagen 1α1 secretion, and partially restored mitochondrial respiratory capacity. In 3D spheroids, it preserved viability, attenuated caspase-3/7 activation, and suppressed procollagen 1α1 release. In cardiac microtissues, elafibranor reduced ECM accumulation, shifted transcriptomic profiles toward redox-metabolic/cytoprotective pathways, altered adenine nucleotide and NAD pools, and partially recovered contraction parameters. In hiPSC-derived cardiomyocytes, elafibranor modulated calcium handling, contractility, and mitochondrial respiration. Conclusions Elafibranor mitigates TGF-β 1 -driven cardiac fibrosis by suppressing fibroblast activation and ECM remodelling while promoting adaptive metabolic, redox, and bioenergetic responses, supporting balanced PPAR-α/δ activation as a potential therapeutic strategy for cardiac fibrosis. Graphical abstract

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