BACKGROUND: The adult mammalian heart is incapable of regeneration, whereas a transient regenerative capacity is maintained in the neonatal heart, primarily through the proliferation of preexisting cardiomyocytes. Neonatal heart regeneration after myocardial injury is accompanied by an expansion of cardiac fibroblasts and compositional changes in the extracellular matrix. Whether and how these changes influence cardiomyocyte proliferation and heart regeneration remains to be investigated. METHODS: We used apical resection and myocardial infarction surgical models in neonatal and adult mice to investigate extracellular matrix components involved in heart regeneration after injury. Single-cell RNA sequencing and liquid chromatography–mass spectrometry analyses were used for versican identification. Cardiac fibroblast–specific Vcan deletion was achieved using the mouse strains Col1a2-2A-CreER and Vcan ^fl/fl . Molecular signaling pathways related to the effects of versican were assessed through Western blot, immunostaining, and quantitative reverse transcription polymerase chain reaction. Cardiac fibrosis and heart function were evaluated by Masson trichrome staining and echocardiography, respectively. RESULTS: Versican, a cardiac fibroblast–derived extracellular matrix component, was upregulated after neonatal myocardial injury and promoted cardiomyocyte proliferation. Conditional knockout of Vcan in cardiac fibroblasts decreased cardiomyocyte proliferation and impaired neonatal heart regeneration. In adult mice, intramyocardial injection of versican after myocardial infarction enhanced cardiomyocyte proliferation, reduced fibrosis, and improved cardiac function. Furthermore, versican augmented the proliferation of human induced pluripotent stem cell–derived cardiomyocytes. Mechanistically, versican activated integrin β1 and downstream signaling molecules, including ERK1/2 and Akt, thereby promoting cardiomyocyte proliferation and cardiac repair. CONCLUSIONS: Our study identifies versican as a cardiac fibroblast–derived pro-proliferative proteoglycan and clarifies the role of versican in promoting adult cardiac repair. These findings highlight its potential as a therapeutic factor for ischemic heart diseases.

Sensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism. IncuCyte S3 was used to explore the difference in the responsiveness of hematological tumor cells and solid tumor cells to GSK126. Transcriptome and metabolome of B16F10 cells after GSK126 treatment were analyzed and the distinct changes in the metabolic profile were revealed. Real-time quantitative PCR and western blot experiments were used to further verify the multi-omics data. ChIP-qPCR was performed to detected H3K27me3 enrichment of target genes. Finally, the anti-tumor effects of combining GSK126 and lipid metabolism drugs were observed with IncuCyte S3 platform, CCK-8 and animal model respectively. We found that although the proliferative phenotype did not show strong difference upon treatment with GSK126, the transcriptome and metabolome changed profoundly. GSK126 treatment led to broad shifts in glucose, amino acid, and lipid metabolism. Lipid synthesis was strengthened manifested by the increasing abundance of unsaturated fatty acids. SCD1 and ELOVL2 were regulated by H3K27me3 at gene regulatory region, and upregulated by EZH2 knockdown and inhibitors. SCD1 knockdown increased cellular sensitivity to GSK126. Based on the findings above, the application of the combination with SCD1 inhibitor significantly attenuated the proliferation of cancer and increased the sensitivity to GSK126 by suppressing desaturation of fatty acids. Dysregulated lipid metabolism can blunt the sensitivity of cancer cells to GSK126. These characteristics shed light on the novel combination therapy strategies to combat tumor resistance. National Natural Science Foundation of China (No. 81672091, No.91749107 and No. 81972966).

Telmisartan, an angiotensin II type 1 receptor blocker with established anti-inflammatory and antihypertensive properties, has been reported to inhibit tumor cell proliferation, yet its impact on the tumor immune microenvironment remains poorly understood. In this study, we evaluated the immunomodulatory effects of telmisartan using a syngeneic MC38 colorectal cancer model in C57BL/6 mice. Daily intragastric administration of telmisartan significantly suppressed tumor growth and reduced endpoint tumor weight compared with controls. To elucidate the underlying mechanisms, we performed single-cell RNA sequencing on tumor-infiltrating CD45⁺ immune cells and revealed a macrophage-dominated immune landscape comprising multiple transcriptionally distinct subclusters. Telmisartan broadly downregulated pro-tumoral and M2-associated macrophage programs, including decreased expression of genes such as Mrc1 and Spp1, while also suppressing cell proliferation-related pathways. In contrast to its overall suppressive impact on macrophages, telmisartan increased the proportion of cytotoxic CD8⁺ T cells, reduced regulatory T cell counts, and enhanced major histocompatibility complex class I antigen presentation, consistent with an immune-activating effect. These results indicate that telmisartan reshapes the colorectal tumor immune microenvironment by simultaneously attenuating tumor-promoting macrophage activity and augmenting cytotoxic T cell responses. Overall, this study provides a single-cell framework to understand how angiotensin receptor blockade reshapes tumor-infiltrating immune programs, highlighting the translational potential of repurposing telmisartan for novel cancer immunotherapy strategies.