Myocardial infarction (MI) remains a leading cause of mortality worldwide, yet effective cardioprotective strategies remain limited in clinical settings. Vascular endothelial growth factor B (VEGFB) has emerged as a promising therapeutic candidate in MI, but the role of its co-receptor, Neuropilin-1 (NRP1), in cardiomyocyte (CM) survival under ischemic stress remains poorly understood. Here, we investigated VEGFB-NRP1 signaling using an in vivo zebrafish model of cardiac injury as well as in vitro hypoxia models in CMs. We demonstrated that VEGFB overexpression conferred protection against ischemic injury and enhanced cardiac regeneration in the zebrafish heart. Mechanistically, we showed that VEGFB treatment enhances CM viability through reducing reactive oxygen species (ROS), ferroptosis activation, and preserving mitochondrial integrity. We also demonstrated that NRP1 knockdown in the CMs abolished the VEGFB-mediated protective effects, indicating the significant role of NRP1 signaling in VEGFB-induced cardioprotective effects in MI. Lastly, using transcriptome analysis, we confirmed that VEGFB induces anti-apoptotic and anti-ferroptosis gene programs in CMs in response to hypoxic stress. Collectively, our findings provide mechanistic insight into cell death activation pathways, including ferroptosis, in response to ischemic stress and further validate the therapeutic potential of VEGFB in promoting CM survival in ischemic heart disease.

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a 5-year survival rate of 3.2% in metastatic cases. Cisplatin, a DNA-damaging agent, offers minimal benefit due to PDAC’s altered DNA repair and protective stroma. Tumor Treating Fields (TTFields), low intensity alternating electric fields that disrupt mitosis, have shown promise in other solid tumors. We investigated whether TTFields enhance cisplatin efficacy in PDAC and explored the underlying biology.MethodsPDAC cell lines were treated with TTFields and cisplatin alone or in combination. Assays assessed viability, migration, and clonogenic survival. Orthotopic mouse models evaluated tumor volume. Mechanistic studies included KRAS signaling analysis and RNA sequencing.ResultsTTFields significantly reduced PDAC cell viability, migration, and clonogenic survival, with the strongest effects in combination with cisplatin. In vivo, combined therapy achieved ~85% tumor volume reduction. Molecular profiling revealed suppression of KRAS-driven signaling, stromal activation, and survival pathways beyond single-agent effects. Transcriptomic analysis showed alteration of immunogenic tumor microenvironment, downregulation of inflammatory survival signaling, and upregulation of genes linked to cytoskeletal and mitochondrial remodeling, changes predicted to limit tumor spread and promote apoptosis.ConclusionsTTFields potentiate cisplatin’s therapeutic impact in PDAC and reveal a novel biology where electrical and chemical stress converge to reprogram tumor survival. This well tolerated multimodal strategy offers a promising avenue for improving outcomes in PDAC, a cancer urgently needing more effective treatments.