Targeting Hsc70-mediated mitochondrial-lipid droplet crosstalk via Ginsenoside Rb2 promotes post-infarction cardiomyocyte regeneration.

Inducing adult cardiomyocyte proliferation to repair the infarcted heart remains a major therapeutic challenge. While metabolic reprogramming is known to drive regeneration, the specific organelle-level mechanisms governing this process, particularly the crosstalk between mitochondria and lipid droplets (LDs), remain elusive. Here, we identify Heat Shock Cognate 71 kDa Protein (Hsc70) as a critical physiological "metabolic brake" that maintains adult cardiomyocytes in a terminally differentiated state and suppresses cell cycle re-entry by tethering mitochondria to LDs via Mitofusin 2 (Mfn2). Using Ginsenoside Rb2, a bioactive small molecule identified from a clinically effective formula (Shuangshen Ningxin), we demonstrate that Rb2 directly binds to Hsc70 (KD ≈ 32 µM) and disrupts the Hsc70-Mfn2 interaction. This disruption pharmacologically uncouples the remaining mitochondria-LD contacts to f release this physiological barrier, restores metabolic homeostasis, and reactivates cardiomyocyte proliferation in myocardial infarction (MI) rats. Crucially, these regenerative effects were abrogated by AAV9-mediated Hsc70 overexpression, confirming Hsc70 as the non-redundant therapeutic target. Furthermore, a retrospective analysis of 60 patients treated with the Rb2-containing intervention showed significantly improved cardiac outcomes, highlighting the broad cardioprotective and clinical utility of this therapeutic strategy. Our findings reveal a fundamental mechanism linking organelle dynamics to tissue regeneration and highlight Hsc70 as a druggable target for heart failure treatment.