Ginkgolide B drives cardiomyocyte proliferation and myocardial regeneration through TLR4/NF-κB/HIF-1α-regulated glycolytic reprogramming.
Abstract
Background
Myocardial infarction (MI) continues to contribute substantially to global mortality and is characterized by irreversible cardiomyocyte loss and limited regenerative capacity in the adult heart. Ginkgolide B (GB), a bioactive compound used in traditional Chinese medicine, has well-documented cardioprotective effects; however, whether it promotes cardiomyocyte proliferation and myocardial regeneration, and through which mechanisms, remains unclear.
Purpose
This study aimed to investigate the therapeutic potential and underlying molecular mechanisms of GB in promoting cardiomyocyte proliferation and cardiac regeneration.
Methods
The therapeutic effects of GB were assessed in cardiomyocyte (CM) cell lines and mouse models of apical resection (AR) and MI. To define the underlying mechanism, we combined network pharmacology, molecular docking, molecular dynamics simulations, RNA sequencing, and targeted metabolite profiling. The interaction between GB and TLR4 was evaluated using a cellular thermal shift assay (CETSA). The dependency on the TLR4/NF-κB/HIF-1α pathway and glycolysis were pharmacologically validated using 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) and Bay 11-7082 (NF-κB inhibitor).
Results
GB enhanced CM proliferation and angiogenesis in vitro, and improved cardiac function, reduced infarct size, and promoted CM proliferation in neonatal and adult mouse models. Mechanistically, GB interacted directly with TLR4, activated the NF-κB/HIF-1α signaling axis, and promoted a shift toward glycolytic metabolism. Inhibition of NF-κB or glycolysis abolished GB-induced CM proliferation, glycolytic activity, and myocardial regeneration.
Conclusions
GB promotes cardiomyocyte proliferation and cardiac regeneration through TLR4/NF-κB/HIF-1α-dependent regulation of glycolytic metabolism. These findings support the potential of GB as a plant-derived therapeutic candidate for ischemic heart disease.