Radix Rehmanniae Preparata polysaccharide promoted zebrafish heart regeneration by activating the IFN-γ/NF-κB signaling axis.

Radix Rehmanniae Praeparata polysaccharide (RRPP), a primary bioactive component of the traditional Chinese medicine Rehmannia, possesses diverse pharmacological activities including immunomodulatory effects. While its cardioprotective potential has been noted, the role of RRPP in promoting cardiac regeneration and the underlying mechanisms remain largely unexplored. Using a zebrafish cardiac cryoinjury model, we demonstrated that RRPP administration significantly enhanced heart regeneration by promoting cardiomyocyte proliferation and dedifferentiation. This regenerative effect was coupled with an accelerated inflammatory response, marked by increased infiltration of L-Plastin(+) leukocytes and T cells, and a rapid induction of IFN-γ expression at the injury site. Disruption of IFN-γ signaling, either pharmacologically with the antagonist creatine or genetically in ifng1r(+/−) heterozygous mutants, severely impaired innate regenerative capacity and abrogated the benefits of RRPP. Transcriptomic profiling revealed that RRPP activates the NOD-like receptor (NLR) signaling pathway, which is associated with the upregulation of NF-κB. Crucially, pharmacological inhibition of NF-κB with aspirin attenuated heart regeneration, and this inhibition was effectively rescued by co-treatment with RRPP. Our findings unveil a novel mechanism whereby RRPP facilitates zebrafish heart regeneration, which is associated with the orchestration of an inflammatory response centered on the IFN-γ/NF-κB signaling axis. This study not only elucidates a pro-regenerative function of RRPP but also highlights the potential of modulating specific inflammatory pathways as a therapeutic strategy for heart repair. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13062-026-00731-5.