The dual PPAR-α/δ agonist elafibranor attenuates TGF-β1-induced cardiac fibrosis through redox-metabolic and bioenergetic reprogramming in human cardiac models

Paw, M.; Minder, L.; Laimbacher, A.; Czepiec, M.; Bobis-Wozowicz, S.; Wnuk, D.; Kutryb-Zajac, B.; Braczko, A.; Sarna, M.; Kaczara, P.; Chłopicki, S.; Madeja, Z.; Distler, O.; Błyszczuk, P.; Czyz, J.; Kania, G.

doi:10.64898/2026.08.18.745425

bioRxiv · 10.64898/2026.08.18.745425

The dual PPAR-α/δ agonist elafibranor attenuates TGF-β1-induced cardiac fibrosis through redox-metabolic and bioenergetic reprogramming in human cardiac models

Paw, M.·Minder, L.·Laimbacher, A.·Czepiec, M.·Bobis-Wozowicz, S.·Wnuk, D.·Kutryb-Zajac, B.·Braczko, A.·Sarna, M.·Kaczara, P.·Chłopicki, S.·Madeja, Z.·Distler, O.·Błyszczuk, P.·Czyz, J.·Kania, G.

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Abstract

BackgroundCardiac 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-/{delta} agonist approved for the treatment of liver disease. However, its effects in human models of cardiac fibrosis remain insufficiently explored. MethodsElafibranor was evaluated in complementary human in vitro TGF-{beta}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. ResultsAt non-cytotoxic concentrations, elafibranor attenuated TGF-{beta}1-driven cardiac fibrosis responses. In 2D cardiac fibroblasts, it reduced myofibroblast differentiation, procollagen 11 secretion, and partially restored mitochondrial respiratory capacity. In 3D spheroids, it preserved viability, attenuated caspase-3/7 activation, and suppressed procollagen 11 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. ConclusionsElafibranor mitigates TGF-{beta}1-driven cardiac fibrosis by suppressing fibroblast activation and ECM remodelling while promoting adaptive metabolic, redox, and bioenergetic responses, supporting balanced PPAR-/{delta} activation as a potential therapeutic strategy for cardiac fibrosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/745425v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@2de670org.highwire.dtl.DTLVardef@173fea6org.highwire.dtl.DTLVardef@537e7aorg.highwire.dtl.DTLVardef@194b846_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Paw, M., Minder, L., Laimbacher, A., Czepiec, M., Bobis-Wozowicz, S., Wnuk, D., Kutryb-Zajac, B., Braczko, A., Sarna, M., Kaczara, P., Chłopicki, S., Madeja, Z., Distler, O., Błyszczuk, P., Czyz, J., Kania, G.. 2026-08-21. The dual PPAR-α/δ agonist elafibranor attenuates TGF-β1-induced cardiac fibrosis through redox-metabolic and bioenergetic reprogramming in human cardiac models. https://doi.org/10.64898/2026.08.18.745425

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