Doxorubicin (DOX), a widely used chemotherapy agent in cancer treatment, encounters limitations in clinical efficacy due to associated cardiotoxicity. This study aims to explore the role of AKT serine/threonine kinase 2 (AKT2) in mitigating DOX-induced oxidative stress within the heart through both intracellular and extracellular signaling pathways. Utilizing AKT2 knockout (KO) and NRF2 KO murine models, alongside neonatal rat cardiomyocytes (NRCMs), we systematically investigate the impact of AKT2 deficiency on DOX-induced cardiac injury.

Our findings reveal that DOX administration induces significant oxidative stress, a primary contributor to cardiac injury. Importantly, Akt2 deficiency exhibits a protective effect by alleviating DOX-induced oxidative stress. Mechanistically, Akt2 deficiency facilitates nuclear translocation of NRF2, thereby suppressing intracellular oxidative stress by promoting the expression of antioxidant genes. Furthermore, We also observed that AKT2 inhibition facilitates superoxide dismutase 2 (SOD2) expression both inside macrophages and SOD2 secretion to the extracellular matrix, which is involved in lowering oxidative stress in cardiomyocytes upon DOX stimulation.

The present study underscores the important role of AKT2 in mitigating DOX-induced oxidative stress through both intracellular and extracellular signaling pathways. Additionally, our findings propose promising therapeutic strategies for addressing DOX-induced cardiomyopathy in clinic.

阿霉素 (DOX) 是一种广泛用于癌症治疗的化疗药物，但由于相关的心脏毒性而导致临床疗效受到限制。本研究旨在探讨 AKT 丝氨酸/苏氨酸激酶 2 (AKT2) 通过细胞内和细胞外信号通路减轻 DOX 诱导的心脏内氧化应激的作用。利用 AKT2 敲除 (KO) 和 NRF2 KO 小鼠模型以及新生大鼠心肌细胞 (NRCM)，我们系统地研究了 AKT2 缺陷对 DOX 诱导的心脏损伤的影响。

我们的研究结果表明，DOX 给药会引起显着的氧化应激，这是心脏损伤的主要原因。重要的是，Akt2缺陷可通过减轻 DOX 诱导的氧化应激发挥保护作用。从机制上讲，Akt2缺陷会促进 NRF2 的核转位，从而通过促进抗氧化基因的表达来抑制细胞内氧化应激。此外，我们还观察到 AKT2 抑制促进巨噬细胞内超氧化物歧化酶 2 (SOD2) 的表达以及 SOD2 分泌到细胞外基质，这参与降低 DOX 刺激后心肌细胞的氧化应激。

本研究强调了 AKT2 通过细胞内和细胞外信号通路减轻 DOX 诱导的氧化应激的重要作用。此外，我们的研究结果提出了在临床上解决 DOX 诱发的心肌病的有前景的治疗策略。