Liquorice and dried ginger decoction alleviates Doxorubicin-Induced Cardiotoxicity by regulating ferroptosis through targeting PKA to modulate C/EBPβ/ACSL4 signaling

Background and Purpose: Liquorice and dried ginger decoction (LGD) is a famous classic prescription. However, there has been no report on the effect of LGD against doxorubicin-induced cardiotoxicity (DIC). To examine whether LGD has possible beneficial effects against DIC by regulating ferroptosis through targeting PKA to modulate C/EBPβ/ACSL4 signaling. Experimental Approach: 50 mice were split into five groups. For 4 weeks, doxorubicin (DOX) was administered at a dose of 2.5 mg/kg twice per week intraperitoneally except the CON group while the doses of LGD were gavaged based on our established protocol except the CON group and the DOX group. The cardioprotective effect of LGD on DIC in mice was evaluated through assessment of cardiac function, tissue pathology and ultrastructure changes. Iron deposition was also investigated by using Prussian blue staining. Furthermore, we determined the levels of proteins associated with ferroptosis were determined by western blot and verified whether the cardioprotective effect of the LGD is mediated through targeting PKA to regulate the C/EBPβ/ACSL4 signaling pathway. Key Results: LGD significantly improved cardiac function, attenuated cardiac [tissue injury](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/tissue-injury), and reduced DOX-induced myocardial apoptosis. Serum CK-MB, LDH1, IL-1β and TNF-α were decreased, oxidative stress mitigated, and iron deposition reduced. Western blot analysis showed that significantly increased PKA, C/EBPβ, GPX4 and SLC7A11 levels, and decreased ACSL4 levels in LGD‑treated mice. Conclusion and Implications: Considered as a whole, we can see that the ability of LGD against DIC is likely facilitated through targeting PKA to modulate the C/EBPβ/ACSL4 signaling pathway to regulate ferroptosis.