Objective: To investigate whether Gastrodin (Gas) attenuates doxorubicin (Dox)-induced cardiomyocyte senescence and apoptosis by regulating the AMPK/mTOR/4EBP1 signaling pathway and autophagy-related processes. Methods: A Dox-induced senescence model was established in H9c2 cardiomyocytes, and different concentrations of Gas (0.5 mM and 1 mM) were used for intervention. Senescence phenotypes were evaluated using SA-β-gal staining and senescence-associated proteins (P16, P21, and P53). Furthermore, the autophagy inhibitor 3-MA and the AMPK inhibitor Compound C (CC) were applied. Combined with Western blotting, Annexin V/PI flow cytometry, and immunofluorescence techniques, the expression levels of senescence-related proteins, autophagy-related markers (LC3-II/I, Beclin-1, and p62), and the phosphorylation levels of key proteins in the AMPK/mTOR/4EBP1 signaling pathway were analyzed to explore the potential mechanism of Gas. Results: Compared with the Dox model group, Gas intervention dose-dependently reduced the percentage of SA-β-gal-positive cells, downregulated the protein expression levels of P16, P21, P53, and γ-H2AX, and significantly inhibited apoptosis. Mechanistically, Gas treatment partially ameliorated the abnormalities in autophagy-related markers induced by Dox, as evidenced by increased expression of LC3 and Beclin-1 and decreased accumulation of p62, and this ameliorative effect was partially attenuated by 3-MA. Further signaling pathway analysis demonstrated that Gas significantly increased the p-AMPK/AMPK ratio while decreasing the p-mTOR/mTOR and p-4EBP1/4EBP1 ratios. After AMPK inhibition with CC, the activation effect of Gas on autophagy and its protective effects against senescence and apoptosis were both attenuated. Conclusion: These findings indicate that Gas alleviates Dox-induced cardiomyocyte senescence and apoptosis, and its protective effects may be associated with regulation of the AMPK/mTOR/4EBP1 signaling pathway and improvement of autophagy-related processes.

As the vital power organ of the human body, the health of the heart directly determines an individual's quality of life and longevity. With the accelerating global aging population, cardiac aging-related diseases have become a major public health threat. Although existing interventions (e.g., senolytics) can delay cardiac aging to some extent, their efficacy remains limited, necessitating the exploration of novel mechanisms to develop more effective therapeutic strategies. In recent years, PANoptosis—an integrated cell death pathway—has emerged as a new research focus in cardiac aging. It may contribute to cardiac functional decline by accelerating cardiomyocyte loss, fibrosis, and chronic inflammation. Targeting PANoptosis-based intervention strategies (e.g., gene editing, RNAi, combination therapy, and novel delivery systems) has demonstrated significant therapeutic potential, offering new preclinical avenues to delay or alleviate cardiac aging. This review summarizes the molecular mechanisms and roles of PANoptosis in cardiac aging, including its regulatory networks, key evidence driving cardiac aging, and targeted intervention strategies, thereby providing a theoretical foundation for developing PANoptosis-targeted therapies against cardiac aging.