RND3 (Rho family GTPase 3) is a unique small GTPase that binds GTP but lacks intrinsic GTPase activity and cannot be activated by traditional GTPase-activating proteins 1. Its primary function is to serve as an endogenous antagonist of RhoA signaling, regulating actin cytoskeleton dynamics, cell migration, and neuron polarity 1. Mechanistically, RND3 interacts with key signaling molecules including Rock1 and STAT3 to modulate downstream pathways controlling mitochondrial dynamics and cell survival 23. RND3 demonstrates substantial clinical relevance in multiple disease contexts. In doxorubicin-induced cardiotoxicity, RND3 overexpression protects cardiomyocytes by inhibiting the Rock1/Drp1-mediated mitochondrial fission and subsequent PANoptosis 2. In diabetes-induced cardiomyopathy, RND3 expression is suppressed via the miR-103a-3p pathway, and RND3 restoration alleviates cardiomyocyte senescence through STAT3 degradation 3. Additionally, RND3 expression is downregulated in hepatocellular carcinoma and bladder cancer, where it functions as a tumor suppressor, with restoration of RND3 enhancing chemotherapy sensitivity 45. These findings position the RND3 signaling pathway as a promising therapeutic target for cardioprotection and improving cancer treatment efficacy.