PARP6-dependent vimentin ADP-ribosylation prevents myofibroblast activation in cardiac fibrosis

Sundaresan, S.; Taneja, A.; Kubon, D.; Bhuyar, A.; Keodora, A.; Pedrioli, D. M. L.; Prabhashankar, A. B.; Rao, P. S. M.; Sundaresan, N. R.; Hottiger, M. O.

doi:10.64898/2026.02.18.706611

bioRxiv · 10.64898/2026.02.18.706611

PARP6-dependent vimentin ADP-ribosylation prevents myofibroblast activation in cardiac fibrosis

Sundaresan, S.·Taneja, A.·Kubon, D.·Bhuyar, A.·Keodora, A.·Pedrioli, D. M. L.·Prabhashankar, A. B.·Rao, P. S. M.·Sundaresan, N. R.·Hottiger, M. O.

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Abstract

Cardiac fibrosis is a central driver of adverse remodeling during heart failure, yet the post-translational regulation of myofibroblast activation remains poorly defined. Here, we identified PARP6 as a mono-ADP-ribosyltransferase that repressed myofibroblast activation through the ADP-ribosylation of vimentin. PARP6 expression was reduced in failing human hearts and Parp6 haploinsufficiency in mice was sufficient to induce cardiac fibrosis. At the cellular level, PARP6 ADP-ribosylated vimentin thereby limiting actin stress fiber formation. Mechanistically, PARP6 inhibition enhanced RhoA activation and vimentin-RhoA complex formation, thus activating the RhoA-ROCK-LIMK-cofilin pathway. Consistently, Parp6 haploinsufficiency was associated with increased cofilin phosphorylation in mice hearts. In primary cardiac fibroblasts, PARP6 inhibition promoted RhoA-dependent actin stress fiber accumulation and induced myofibrotic protein expression. Together, these findings define a PARP6-vimentin(ADP-ribosylation)-RhoA axis that restrained contractility-driven fibroblast activation, indicating a cardioprotective role of PARP6 with potential therapeutic relevance for fibrotic heart disease.

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Sundaresan, S., Taneja, A., Kubon, D., Bhuyar, A., Keodora, A., Pedrioli, D. M. L., Prabhashankar, A. B., Rao, P. S. M., Sundaresan, N. R., Hottiger, M. O.. 2026-02-19. PARP6-dependent vimentin ADP-ribosylation prevents myofibroblast activation in cardiac fibrosis. https://doi.org/10.64898/2026.02.18.706611

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