Mechanisms of Doxorubicin-Induced Cardiac Senescence and Potential Therapeutic Strategies

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  Figure 1. DOX-induced cardiac senescence: target cells, mechanisms, and countermeasures. Doxorubicin targets multiple cardiac cell populations, including cardiomyocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells, triggering senescence-related mechanisms, including oxidative stress, mitochondrial dysfunction, telomere dysfunction, senescence-associated secretory phenotype (SASP), non-coding RNA regulation, autophagy, and apoptosis, which collectively promote cellular senescence, cardiac dysfunction, and pathological remodeling. Potential countermeasures to mitigate this senescence progression include mechanism-targeted pharmacological agents, nutritional intervention, exercise training, senolytic intervention, senescent phenotypic inhibition, and Traditional Chinese Medicine. Solid arrows indicate DOX-induced pathological progression, whereas the blunt-ended line indicates the inhibitory effects of the intervention strategies on DOX-induced cardiac senescence. Created in BioRender. Zhang, Z. (2026) https://BioRender.com/um2swv0.

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  Figure 2. Cell-type-specific mechanisms of DOX-induced cardiac and vascular senescence and dysfunction. In cardiomyocytes, p53-p21 activation, p16 upregulation, reduced TRF1/TRF2 expression, C5a/C5aR signaling, and TXNIP-NLRP3-IL-1β activation promote senescence, whereas DRP1 Ser616 phosphorylation and mitochondrial fission/dysfunction contribute to contractile dysfunction. Testosterone-AR-PI3K/AKT/NOS3 signaling preserves TRF2 and inhibits cardiomyocyte senescence. In cardiac fibroblasts, AKT/SMAD phosphorylation and increased expression of α-SMA, MMP1, IL-6, TGF-β, and collagen promote fibroblast activation, while p53-Parkin interaction, impaired mitophagy, p53-p21 activation, and γH2AX accumulation contribute to fibroblast dysfunction and senescence. In endothelial cells, mitochondrial ROS, DNA damage, and NLRP3-IL-1β signaling promote senescence and endothelial dysfunction, whereas vitamin D3-AMPKα/SIRT1/FOXO3a-IL-10 signaling is protective. In VSMCs, uPAR-dependent TRF2 degradation, ROS/DNA damage, and p53/p21 and p16 activation promote senescence and SASP, whereas NOX4 downregulation is associated with, but has not been established as necessary for, DOX-induced senescence. In a…

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  Figure 3. Doxorubicin impairs cardiomyocyte function through three primary pathways: disrupted mitochondrial dynamics, telomere dysfunction and cell-cycle arrest, and oxidative stress and inflammatory signaling. (1) Mitochondrial Dynamics: DOX enhances mitochondrial fission by promoting DRP1 phosphorylation at Ser616. Additionally, DOX-induced downregulation of SIRT6 reduces the expression of the mitochondrial fusion proteins MFN1/2 and OPA1, collectively leading to mitochondrial fragmentation. (2) Telomere Dysfunction and Cell-Cycle Arrest: DOX activates p53–p21 signaling and upregulates p16, leading to cell-cycle arrest. Concurrent downregulation of SIRT6 and the telomere-binding proteins TRF1/2 impairs telomere maintenance and contributes to telomere dysfunction. (3) Oxidative Stress and Inflammatory Signaling: DOX induces oxidative stress by promoting ROS accumulation. It upregulates TXNIP expression and activates the NLRP3 inflammasome. C5a–C5aR signaling further enhances ROS production, accompanied by NF-κB activation and increased TNF-α, IL-1β, and IL-6. Solid black arrows indicate promotion or activation, and “p-” denotes phosphorylation. Created in BioRender. Zhang, Z. (2026)…

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  Figure 4. DOX-induced cardiac senescence involves multiple mechanisms, mainly including the following: (1) Oxidative stress: ROS-mediated redox imbalance represents a key mechanism. (2) Telomere dysfunction: DOX disrupts telomere homeostasis through telomere shortening, reduced telomerase activity, and TRF1/TRF2 downregulation, thereby activating the DNA damage response (DDR). (3) Mitochondrial dysfunction: DOX perturbs mitochondrial fission–fusion dynamics and metabolic function, thereby contributing to cardiac senescence. (4) SASP: low-dose DOX induces the senescence-associated secretory phenotype (SASP), whereas targeting SASP alleviates DOX-induced cardiac senescence. (5) Non-coding RNAs: circ-Foxo3, lincRNA-p21, miR-199a-3p, and other non-coding RNAs modulate cardiac senescence through downstream genes and signaling pathways. (6) Autophagy: activation of autophagy and mitophagy may mitigate DOX-induced cardiac senescence by restoring cellular and mitochondrial quality control. (7) Apoptosis–senescence crosstalk: high-dose DOX preferentially induces apoptosis, whereas lower-dose exposure promotes senescent growth arrest and may lead to delayed cell death. Solid red arrows indicate…